Ether compounds and uses thereof

ABSTRACT

The present invention provides compounds that modulate protein function, to restore protein homeostasis and/or cell-cell adhesion. The invention provides methods of modulating protein-mediated diseases, such as cytokine-mediated diseases, disorders, conditions, or responses. Compositions of these compounds are also provided. Methods of treatment, amelioration, or prevention of protein-mediated diseases, disorders, and conditions are also provided.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all applications for which a foreign or domestic priority claimis identified, for example, in the Application Data Sheet or Request asfiled with the present application, are hereby incorporated by referenceunder 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. ProvisionalApplication No. 62/550,489, filed Aug. 25, 2017.

BACKGROUND Field

Compounds, methods of making such compounds, pharmaceutical compositionsand medicaments comprising such compounds, and methods of using suchcompounds to treat, prevent or diagnose diseases, disorders, orconditions associated with protein malfunction are provided.

Description of the Related Technology

Protein levels are highly regulated in response to physiological cues.In cells, much of protein degradation is carried out by theubiquitin-proteasome system (UPS). Aberrant protein function, and/orprotein imbalance is a hallmark of many disease states. For example,dynamic modulation of key intracellular signaling proteins within theimmune system is required to maintain proper balance of pro-inflammatoryand anti-inflammatory mediators or cytokines. Some cytokines promoteinflammation (pro-inflammatory cytokines), whereas other cytokinessuppress the activity of the pro-inflammatory cytokines(anti-inflammatory cytokines). For example, IL-4, IL-10, and IL-13 arepotent activators of B lymphocytes, and also act as anti-inflammatoryagents. They are anti-inflammatory cytokines by virtue of their abilityto suppress genes for pro-inflammatory cytokines such as interleukin 1(IL-1), interleukin 6 (IL-6), tumor necrosis factor alpha (TNFα), andchemokines.

Unregulated activities of these mediators can lead to the development ofserious inflammatory conditions. For example, autoimmune diseases arisewhen immune system cells (lymphocytes, macrophages) become sensitizedagainst the “self” Lymphocytes, as well as macrophages, are usuallyunder control in this system. However, a misdirection of the systemtoward the body's own tissues may happen in response to stillunexplained triggers. One hypothesis is that lymphocytes recognize anantigen which mimics the “self” and a cascade of activation of differentcomponents of the immune system takes place, ultimately leading totissue destruction. Genetic predisposition has also been postulated tobe responsible for autoimmune disorders.

TNFα, IL-6, and IL-1 are pro-inflammatory cytokines that mediateinflammatory responses associated with infectious agents and othercellular stresses. Overproduction of these cytokines is believed tounderlie the progression of many inflammatory diseases includingrheumatoid arthritis (RA), Crohn's disease, inflammatory bowel disease,multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease,congestive heart failure, and psoriasis among others.

Recent data from clinical trials support the use of protein antagonistsof cytokines, for example soluble TNFα receptor fusion protein(etanercept) or the monoclonal TNFα antibody (infliximab), for thetreatment of rheumatoid arthritis, Crohn's disease, juvenile chronicarthritis and psoriatic arthritis. Thus, the reduction ofpro-inflammatory cytokines such as TNFα, IL-6, and IL-I has become anaccepted therapeutic approach for potential drug intervention in theseconditions.

Moreover, IL-2 is now FDA approved for the treatment of renal cancer andmelanoma patients, with durable, complete remissions achieved with IL-2up to 148 months. However, the short half-life of IL-2 in serum requiresthat large amounts of IL-2 be injected to achieve therapeutic levels.Many attempts have been made to minimize side effects of systemic IL-2treatment, for example, introducing IL-2 directly into the tumor, thoughthis complicates treatment, and has largely been unsuccessful.

Local delivery of cytokines is appealing compared to systemic deliveryfor a variety of reasons. It takes advantage of the natural biology ofcytokines that have evolved to act locally in a paracrine or autocrinefashion. Local expression also dramatically minimizes many of the sideeffects of systemic delivery of cytokines. Thus, compounds and methodsto increase local expression of IL-2 would be better tolerated than highdose IL-2 treatment, which would expand therapeutic utility ofstrategies that increase IL-2.

Additional targets include several candidate genes involved in apoptosisand cell survival, including casein kinase 1α (CK1α) and the zinc-fingertranscription factors aiolos, helios, and ikaros. Aiolos, helios, andikaros are transcription factors whose expression is restricted tolymphoid lineages. For example, aiolos binds to the Bcl-2 promoter, andalso interacts with the Bcl-2 and Bcl-XL proteins to promote cellsurvival. Upregulation of aiolos expression, for example, can reduceapoptosis of HIV-1 infected cells.

Likewise, expression of aiolos in lung and breast cancers predictssignificantly reduced patient survival. Aiolos decreases expression of alarge set of adhesion-related genes, disrupting cell-cell andcell-matrix interactions, facilitating metastasis. Aiolos may alsofunction as an epigenetic driver of lymphocyte mimicry in certainmetastatic epithelial cancers. Similarly, aberrant ikaros and heliosexpression may promote Bcl-XL expression, driving the development ofhematopoietic malignancies. Thus, down-regulation of aiolos, ikaros,and/or helios may reduce or eliminate metastasis.

Casein kinase 1α (CK1α) is a component of the β-catenin-degradationcomplex and a critical regulator of the Wnt signaling pathway, and itsablation induces both Wnt and p53 activation. Schittek and Sinnberg,Mol. Cancer. 2014, 13, 231; Cheong and Virshup, J. Biochem. Cell Biol.2011, 43, 465-469; Elyada et al., Nature 2011, 470, 409-413. CK1αphosphorylates β-catenin, which is subsequently further phosphorylatedby GSK-3β. This destabilizes β-catenin and marks the protein forubiquitination and proteosomal degradation. Thus, CK1α functions as amolecular switch for the Wnt pathway. Amit et al., Genes Dev. 2002, 16,1066-1076. CK1α is critical for embryogenesis and plays an importantrole in tissue development and response to DNA damage, at least partlycoordinated with p53. Elyada et al., Nature 2011, 470, 409-413;Schneider et al., Cancer Cell 2014, 26, 509-520. Levine and Oren, Nat.Rev. Cancer 2009, 9, 749-758.

Indeed, CK1α also phosphorylates p53, which inhibits binding to MDM2 (ap53 inhibitor) and stabilizes p53's binding interactions with thetranscriptional machinery. Huart, et al., J. Biol. Chem. 2009, 284,32384-32394. Thus, inhibiting CK1α activity increases cellular levels ofp53.

One mechanism to disrupt protein drivers of disease is to decrease thecellular concentration of these proteins. For example, regulatedproteolytic degradation of cellular proteins is essential to normal cellfunction. Hijacking this process, by targeting specific disease-relatedproteins, presents a novel mechanism for the treatment of disease. Theirreversible nature of proteolysis makes it well-suited to serve as aregulatory switch for controlling unidirectional processes. For example,Ikaros is a transcriptional repressor of IL-2 expression. Accordingly, areduction in Ikaros protein levels leads to enhanced IL-2 expression inactivated T cells. IL-2 therapy is currently being evaluated for a widearray of clinical indications, including for treatment of systemic lupuserythematosus (SLE), wound healing, and immune-oncology.

SUMMARY OF THE INVENTION

Some embodiments provide a compound of Formula (I), or apharmaceutically acceptable salt thereof:

In some embodiments, Q₁ can be CH₂, O, NR₂, S, or a bond.

In some embodiments, Q₂ can be CH₂ or a bond.

In some embodiments, X can be CH₂ or C═O.

In some embodiments, X₁ can be hydrogen, deuterium, methyl, or fluoro.

In some embodiments, Ring B can be

wherein Y₁ is N or CR_(3A), Y₂ is N or CR_(3B), Y₃ is N or CR_(3C), Y₄is N or CR_(3D), and Y₅ is N or CR_(3E).

In some embodiments, each R₁ can be independently deuterium, hydroxyl,halogen, nitro, a substituted or unsubstituted amino, a substituted orunsubstituted C₁-C₆ alkoxy, a substituted or unsubstituted C₁-C₆ alkyl,a substituted or unsubstituted C₂-C₆ alkenyl, a substituted orunsubstituted C₃-C₈ cycloalkyl, a substituted or unsubstituted 3 to 10membered heterocyclyl, a substituted or unsubstituted C₆-C₁₀ aryl, asubstituted or unsubstituted 5 to 10 membered heteroaryl, or L-Y.

In some embodiments, R₂ can be hydrogen, deuterium, a substituted orunsubstituted C₁-C₆ alkyl, a substituted or unsubstituted C₂-C₆ alkenyl,acyl, or —(SO₂)—C₁-C₆ alkyl.

In some embodiments, each of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be independently hydrogen, deuterium, hydroxyl, halogen, nitro, asubstituted or unsubstituted amino, a substituted or unsubstituted C₁-C₆alkoxy, a substituted or unsubstituted C₁-C₆ alkyl, a substituted orunsubstituted C₂-C₆ alkenyl, a substituted or unsubstituted C₃-C₈cycloalkyl, a substituted or unsubstituted 3 to 10 memberedheterocyclyl, a substituted or unsubstituted alkoxyalkyl, a substitutedor unsubstituted cycloalkylalkyl, a substituted or unsubstitutedheterocyclylalkyl, a substituted or unsubstituted aralkyl, a substitutedor unsubstituted heteroaralkyl, or L-Y.

In some embodiments, m can be 0, 1, 2, or 3.

In some embodiments, n can be 1, 2, 3, or 4. In some embodiments, n canbe 1 or 2.

In some embodiments, L can be —Z₁—(R₄)_(t)—Z₂—; —Z₁—(R₄—O—R₄)_(t)—Z₂—;—Z₁(R₄—NH—R₄)_(t)—Z₂—; —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂—;—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂—; or —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂—.

In some embodiments, Z₁ can be —CH₂NH(CO)—; —NH—; —O—; —CH₂—; —NH(CO)—;—(CO)NH—; —CH₂NH—; —(CO)NHCH₂—; —CH₂CH₂NH—; —NHCH₂—; or —NHCH₂CH₂—.

In some embodiments, Z₂ can be —NH—; —O—; —CH₂—; —NH(CO)—; —(CO)NH—;—CH₂NH—; —NHCH₂—; —(CO)NHCH₂—; —CH₂CH₂NH—; —CH₂NH(CO)—.

In some embodiments, each R₄ can be independently an unsubstituted C₁-C₆alkylene.

In some embodiments, t can be 1, 2, 3, 4, 5, or 6.

In some embodiments, Y can be

wherein Y can be derivatized to attach to L.

In some embodiments, at least one of Y₁, Y₂, Y₃, Y₄, and Y₅ can becarbon (bonded to one of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E),respectively, e.g., CR_(3A), CR_(3B), CR_(3C), CR_(3D), and/or CR_(3E)).

In some embodiments, when Q₁ can be CH₂ or a bond, then one or more ofR_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) cannot be hydrogen. In otherembodiments, when R₁ can be L-Y, none of R_(3A), R_(3B), R_(3C), R_(3D),and R_(3E) can be L-Y. In still other embodiments, when Q₁ is a bond,then m is not 0. In some embodiments, when Q₁ is a bond, R₁ is L-Y. Insome embodiments, when Q₁ can be a bond, X₁ is hydrogen or methyl, andQ₂ is CH₂; then m is not 0. In other embodiments, when Q₁ can be a bond,X₁ can be hydrogen or methyl, and Q₂ can be CH₂; then one of R₁, R_(3A),R_(3B), R_(3C), R_(3D), and R_(3E) is L-Y. In some embodiments, when Q₂can be a bond, Q₁ can be a bond or CH₂.

Some embodiments provide a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Q₁ is CH₂, O,NR₂, S, or a bond; Q₂ is CH₂ or a bond; X is CH₂ or C═O; X₁ is hydrogen,deuterium, or fluoro; Ring B is

wherein Y₁ is N or CR_(3A); Y₂ is N or CR_(3B); Y₃ is N or CR_(3C); Y₄is N or CR_(3D); Y₅ is N or CR_(3E); each R₁ is independently deuterium,hydroxyl, halogen, nitro, a substituted or unsubstituted amino, asubstituted or unsubstituted C₁ to C₆ haloalkyl, a substituted orunsubstituted C₁-C₆ alkoxy, a substituted or unsubstituted C₁-C₆ alkyl,a substituted or unsubstituted C₂-C₆ alkenyl, a substituted orunsubstituted C₃-C₈ cycloalkyl, a substituted or unsubstituted 3 to 10membered heterocyclyl, a substituted or unsubstituted C₆-C₁₀ aryl, asubstituted or unsubstituted 5 to 10 membered heteroaryl, or L-Y; R₂ isHydrogen, deuterium, a substituted or unsubstituted C₁-C₆ alkyl, asubstituted or unsubstituted C₂-C₆ alkenyl, acyl, or —(SO₂)—C₁-C₆ alkyl;each R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) is independentlyhydrogen, deuterium, hydroxyl, halogen, nitro, a substituted orunsubstituted amino, a substituted or unsubstituted C₁ to C₆ haloalkyl,a substituted or unsubstituted C₁-C₆ alkoxy, a substituted orunsubstituted C₁-C₆ alkyl, a substituted or unsubstituted C₂-C₆ alkenyl,a substituted or unsubstituted C₃-C₈ cycloalkyl, a substituted orunsubstituted 3 to 10 membered heterocyclyl, a substituted orunsubstituted alkoxyalkyl, a substituted or unsubstitutedcycloalkylalkyl, a substituted or unsubstituted heterocyclylalkyl, asubstituted or unsubstituted aralkyl, a substituted or unsubstitutedheteroaralkyl, or L-Y; m is 0, 1, 2, or 3; n is 1, 2, or 3; L is—Z₁—(R₄—O—R₄)_(t)—Z₂—; —Z₁(R₄—NH—R₄)_(t)—Z₂—;—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂—; —Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂—; or—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂—; Z₁ is —NH—; —O—; —CH₂—; —NH(CO)—; —(CO)NH—;—CH₂NH—; —NHCH₂—; —CH₂NH(CO)—, or —NHCH₂CH₂—; Z₂ is —NH—; —O—; —CH₂—,—NH(CO)—; or —(CO)NH—; —CH₂NH—; —NHCH₂—; or —NHCH₂CH₂—; each R₄ isindependently an unsubstituted C₁-C₆ alkylene; t is 1, 2, 3, 4, 5, or 6;and Y is

wherein Y is derivatized to attach to L; and wherein at least one of Y₁,Y₂, Y₃, Y₄, and Y₅ is respectively R_(3A), R_(3B), R_(3C), R_(3D), orR_(3E); when Q₁ is CH₂ or a bond, then one or more of R_(3A), R_(3B),R_(3C), R_(3D), or R_(3E) is not hydrogen; when R₁ is L-Y, none ofR_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) is L-Y; and when Q₁ is abond, then m is not 0.

In some embodiments, X can be CH₂. In some embodiments, X can be C═O.

In some embodiments, X₁ can be hydrogen. In other embodiments, X₁ can bedeuterium. In still other embodiments, X₁ can be methyl. In someembodiments, X₁ can be fluoro.

In some embodiments, Q₁ can be NR₂. In some embodiments, R₂ can behydrogen. In some embodiments, R₂ can be a substituted or unsubstitutedC₁-C₆ alkyl. In some embodiments, R₂ can be an unsubstituted C₁-C₆alkyl. In some embodiments, R₂ can be acyl. In some embodiments, R₂ canbe —(SO₂)—C₁-C₆ alkyl. In some embodiments, R₂ can be methyl.

In some embodiments, Q₁ can be CH₂. In some embodiments, Q₁ can be 0. Insome embodiments, Q₁ can be S. In some embodiments, Q₁ can be a bond. Insome embodiments, when Q₁ is a bond, then m is not 0. In someembodiments, Q₂ can be CH₂. In some embodiments, Q₂ can be a bond. Insome embodiments, when Q₂ can be a bond, Q₁ can be a bond or CH₂.

In some embodiments, n can be 1. In some embodiments, n can be 2. Insome embodiments, n can be 3. In some embodiments, m can be 1. In someembodiments, m can be 2. In some embodiments, m can be 3. In someembodiments, m can be 0.

In some embodiments, each R₁ can be independently halogen, a substitutedor unsubstituted amino, a substituted or unsubstituted C₁-C₆ alkoxy or asubstituted or unsubstituted C₁-C₆ alkyl. In some embodiments, each R₁can be independently halogen, an unsubstituted amino, an unsubstitutedC₁-C₆ haloalkyl, an unsubstituted C₁-C₆ alkoxy or unsubstituted C₁-C₆alkyl.

In some embodiments, each R₁ can be independently fluoro, chloro, —NH₂,—NH(CH₃), —N(CH₃)₂, —CF₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —CH₃, —CH₂CH₃ or—CH(CH₃)₂.

In some embodiments, Ring B can be selected from:

In some embodiments, each of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be independently hydrogen, deuterium, hydroxyl, halogen, nitro, asubstituted or unsubstituted amino, a substituted or unsubstituted C₁-C₆alkoxy, a substituted or unsubstituted C₁-C₆ alkyl, a substituted orunsubstituted C₂-C₆ alkenyl, a substituted or unsubstituted C₃-C₈cycloalkyl, a substituted or unsubstituted 3 to 10 memberedheterocyclyl, a substituted or unsubstituted alkoxyalkyl, a substitutedor unsubstituted cycloalkylalkyl, a substituted or unsubstitutedheterocyclylalkyl, a substituted or unsubstituted aralkyl or asubstituted or unsubstituted heteroaralkyl.

In some embodiments, each of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be independently hydrogen, hydroxyl, halogen, nitro, anunsubstituted amino, an unsubstituted C₁-C₆ haloalkyl, an unsubstitutedC₁-C₆ alkoxy, an unsubstituted C₁-C₆ alkyl, a substituted orunsubstituted C₃-C₈ cycloalkyl, a substituted or unsubstituted 3 to 10membered heterocyclyl, a substituted or unsubstituted alkoxyalkyl, asubstituted or unsubstituted cycloalkylalkyl, a substituted orunsubstituted heterocyclylalkyl, a substituted or unsubstituted aralkylor a substituted or unsubstituted heteroaralkyl.

In some embodiments, each of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be independently hydrogen, hydroxyl, halogen, nitro, anunsubstituted amino, an unsubstituted C₁-C₆ haloalkyl, an unsubstitutedC₁-C₆ alkoxy, an unsubstituted C₁-C₆ alkyl, an unsubstituted C₃-C₈cycloalkyl, an unsubstituted 3 to 10 membered heterocyclyl, anunsubstituted cycloalkylalkyl, unsubstituted 3 to 10 memberedheterocyclylalkyl, unsubstituted aralkyl or unsubstituted 5 to 10membered heteroaralkyl.

In some embodiments, each of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be independently hydrogen, halogen, an unsubstituted C₁-C₆haloalkyl, an unsubstituted C₁-C₆ alkoxy, an unsubstituted C₁-C₆ alkyl,an unsubstituted 3 to 10 membered heterocyclyl, or an unsubstituted 3 to10 membered heterocyclylalkyl.

In some embodiments, one of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be halogen, an unsubstituted C₁-C₆ haloalkyl, an unsubstituted C₁-C₆alkoxy, an unsubstituted C₁-C₆ alkyl, an unsubstituted 3 to 10 memberedheterocyclyl, or an unsubstituted 3 to 10 membered heterocyclylalkyl andthe other of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) are hydrogen.

In some embodiments, one of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be fluoro, chloro, —CF₃, —OCH₃, an unsubstituted C₁-C₆ alkyl, anunsubstituted 3 to 10 membered heterocyclyl, or an unsubstituted 3 to 10membered heterocyclylalkyl and the other of R_(3A), R_(3B), R_(3C),R_(3D), and R_(3E) are hydrogen.

In some embodiments, one of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be

and the other of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) arehydrogen.

In some embodiments, one R₁ can be L-Y. In some embodiments, one ofR_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be L-Y. In someembodiments, Y₃ can be C-L-Y.

In some embodiments, L can be —Z₁—(R₄)_(t)—Z₂—. In other embodiments, Lcan be —Z₁—(R₄—O—R₄)_(t)—Z₂—. In still other embodiments, L can be—Z₁(R₄—NH—R₄)_(t)—Z₂—. In some embodiments, L can beZ₁—(R₄—(NHCO)—R₄)_(t)—Z₂—. In some embodiments, L can be—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂—. In other embodiments, L can be—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂—.

In some embodiments, Z₁ can be —CH₂NH(CO)—. In other embodiments, Z₁ canbe —NH—. In still other embodiments, Z₁ can be —O—. In some embodiments,Z₁ can be —CH₂—. In other embodiments, Z₁ can be —NH(CO)—. In stillother embodiments, Z₁ can be —CH₂NH—. In some embodiments, Z₁ can be—NHCH₂—. In other embodiments, Z₁ can be —(CO)NH—. In still otherembodiments, Z₁ can be —NHCH₂CH₂—. In some embodiments, Z₁ can be—(CO)NHCH₂—. In still other embodiments, Z₁ can be —CH₂CH₂NH—.

In some embodiments, Z₂ can be —NH—. In other embodiments, Z₂ can be—O—. In still other embodiments, Z₂ can be —CH₂—. In some embodiments,Z₂ can be —NH(CO)—. In other embodiments, Z₂ can be —(CO)NH—. In stillother embodiments, Z₂ can be —CH₂NH—. In some embodiments, Z₂ can be—NHCH₂—. In other embodiments, Z₂ can be —(CO)NH—. In still otherembodiments, Z₂ can be —NHCH₂CH₂—. In some embodiments, Z₂ can be—(CO)NHCH₂—. In other embodiments, Z₂ can be —CH₂CH₂NH—. In still otherembodiments, Z₂ can be —CH₂NH(CO)—.

In some embodiments, each R₄ can be independently an unsubstituted C₁-C₄alkylene. In some embodiments, each R₄ can be independently anunsubstituted C₁-C₂ alkylene.

In some embodiments, t can be 1. In some embodiments, t can be 2. Insome embodiments, t can be 3. In some embodiments, t can be 4. In someembodiments, t can be 5. In some embodiments, t can be 6.

In some embodiments, the compound of Formula (I) is selected from:

or a pharmaceutically acceptable salt of any of the foregoing.

Some embodiments provide a pharmaceutical composition comprising acompound of Formula (I), or a pharmaceutically acceptable salt thereof;and a pharmaceutically acceptable excipient.

Some embodiments provide a method of inhibiting the activity of acytokine, comprising contacting a cell with an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof.Other embodiments provide the use of a compound of Formula (I), or apharmaceutically acceptable salt of any of the foregoing, for inhibitingthe activity of a cytokine, comprising contacting a cell with aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt of any of the foregoing. Still other embodiments providethe use of a compound of Formula (I), or a pharmaceutically acceptablesalt of any of the foregoing, for the manufacture a medicament forinhibiting the activity of a cytokine, comprising contacting a cell withan effective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt of any of the foregoing. In some embodiments, thecytokine is selected from: IL-1β, IL-2, IL-6, and TNFα. In someembodiments, the cytokine is TNFα. In some embodiments, the cell is acancer cell.

Some embodiments provide a method of inhibiting the activity of aiolos,comprising contacting a cell with an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. Otherembodiments provide the use of a compound of Formula (I), or apharmaceutically acceptable salt of any of the foregoing, for inhibitingthe activity of aiolos, comprising contacting a cell with an effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt of any of the foregoing. Still other embodiments provide the use ofa compound of Formula (I), or a pharmaceutically acceptable salt of anyof the foregoing, for the manufacture a medicament for inhibiting theactivity of aiolos, comprising contacting a cell with an effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt of any of the foregoing. In some embodiments, the cell is a cancercell.

Some embodiments provide a method of inhibiting the activity of ikaros,comprising contacting a cell with an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. Otherembodiments provide the use of a compound of Formula (I), or apharmaceutically acceptable salt of any of the foregoing, for inhibitingthe activity of ikaros, comprising contacting a cell with an effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt of any of the foregoing. Still other embodiments provide the use ofa compound of Formula (I), or a pharmaceutically acceptable salt of anyof the foregoing, for the manufacture a medicament for inhibiting theactivity of ikaros, comprising contacting a cell with an effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt of any of the foregoing. In some embodiments, the cell is a cancercell.

Some embodiments provide a method of inhibiting the activity of helios,comprising contacting a cell with an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. Otherembodiments provide the use of a compound of Formula (I), or apharmaceutically acceptable salt of any of the foregoing, for inhibitingthe activity of helios, comprising contacting a cell with an effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt of any of the foregoing. Still other embodiments provide the use ofa compound of Formula (I), or a pharmaceutically acceptable salt of anyof the foregoing, for the manufacture a medicament for inhibiting theactivity of helios, comprising contacting a cell with an effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt of any of the foregoing. In some embodiments, the cell is a cancercell.

Some embodiments provide a method of inhibiting the activity of CK-1α,comprising contacting a cell with an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. Otherembodiments provide the use of a compound of Formula (I), or apharmaceutically acceptable salt of any of the foregoing, for inhibitingthe activity of CK-1α, comprising contacting a cell with an effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt of any of the foregoing. Still other embodiments provide the use ofa compound of Formula (I), or a pharmaceutically acceptable salt of anyof the foregoing, for the manufacture a medicament for inhibiting theactivity of CK-1α, comprising contacting a cell with an effective amountof a compound of Formula (I), or a pharmaceutically acceptable salt ofany of the foregoing. In some embodiments, the cell is a cancer cell.

In some embodiments, the cell is a small cell lung cancer cell, anon-small cell lung cancer cell, a breast cancer cell, a prostate cancercell, a head and neck cancer cell, a pancreatic cancer cell, a coloncancer cell, a rectal cancer cell, a teratoma cell, an ovarian cancercell, an endometrial cancer cell, a brain cancer cell, a retinoblastomacell, a leukemia cell, a skin cancer cell, a melanoma cell, a squamouscell carcinoma cell, a liposarcoma cell, a lymphoma cell, a multiplemyeloma cell, a testicular cancer cell, a liver cancer cell, anesophageal cancer cell, a kidney carcinoma cell, an astrogliosis cell, arelapsed/refractory multiple myeloma cell, or a neuroblastoma cell.

Some embodiments provide a method of treating, ameliorating, orpreventing a disease, disorder, or condition associated with a proteinin a subject, the protein selected from a cytokine, aiolos, ikaros,helios, CK1α, and combinations of any of the foregoing; the methodcomprising administering a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition comprising a compound of Formula (I), ora pharmaceutically acceptable salt thereof, to the subject. Otherembodiments provide the use of a compound of Formula (I), or apharmaceutically acceptable salt of any of the foregoing, for treating,ameliorating, or preventing a disease, disorder, or condition associatedwith a protein selected from a cytokine, aiolos, ikaros, helios, CK1α,and combinations of any of the foregoing. Still other embodimentsprovide the use of a compound of Formula (I), or a pharmaceuticallyacceptable salt of any of the foregoing, for the manufacture amedicament for treating, ameliorating, or preventing a disease,disorder, or condition associated with a protein selected from acytokine, aiolos, ikaros, helios, CK1α, and combinations of any of theforegoing.

In some embodiments, the disease, disorder, or condition is a cancerselected from a hematological malignancy and a solid tumor In someembodiments, the disease, disorder, or condition is a cancer selectedfrom small cell lung cancer, non-small cell lung cancer, breast cancer,prostate cancer, head and neck cancer, pancreatic cancer, colon cancer,rectal cancer, teratoma, ovarian cancer, endometrial cancer, braincancer, retinoblastoma, leukemia, skin cancer, melanoma, squamous cellcarcinoma, liposarcoma, lymphoma, multiple myeloma, testicular cancer,liver cancer, esophageal cancer, kidney carcinoma, astrogliosis,relapsed/refractory multiple myeloma, and neuroblastoma.

In some embodiments, the disease, disorder, or condition is selectedfrom inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis,ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatorybowel diseases, Crohn's disease, ulcerative colitis, uveitis,inflammatory lung diseases, chronic obstructive pulmonary disease, andAlzheimer's disease. In some embodiments, the disease, disorder, orcondition is selected from fibromyalgia, rheumatoid arthritis,osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis,Crohn's disease, and ulcerative colitis.

In some embodiments, the protein is a cytokine. In some embodiments, thecytokine is selected from: IL-1β, IL-2, IL-6, and TNFα. In someembodiments, the cytokine is TNFα. In some embodiments, the protein isaiolos. In some embodiments, the protein is ikaros. In some embodiments,the protein is helios. In some embodiments, the protein is CK1α.

Any of the features of an embodiment is applicable to all embodimentsidentified herein. Moreover, any of the features of an embodiment isindependently combinable, partly or wholly with other embodimentsdescribed herein in any way, e.g., one, two, or three or moreembodiments may be combinable in whole or in part. Further, any of thefeatures of an embodiment may be made optional to other embodiments. Anyembodiment of a method can comprise another embodiment of a compound,and any embodiment of a compound can be configured to perform a methodof another embodiment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents the activity against IL-1-beta in peripheral bloodmononuclear cells (PBMCs), plated in 96 well plates and pretreated withcompound for 1 hour and then induced with 100 ng/mL LPS for 18-24 hrs.Cytokines in the media were measured according to MesoScale protocol.Negative control wells were treated with DMSO. Compound activity ismeasured as a percentage of LPS-induced activity.

FIG. 2 represents the activity against IL-6 in peripheral bloodmononuclear cells (PBMCs), plated in 96 well plates and pretreated withcompound for 1 hour and then induced with 100 ng/mL LPS for 18-24 hrs.Cytokines were measured according to MesoScale protocol. Negativecontrol wells were treated with DMSO. Compound activity was measured asa percentage of LPS-induced activity.

FIG. 3 represents the activity against TNFα in peripheral bloodmononuclear cells (PBMCs), plated in 96 well plates and pretreated withcompound for 1 hour and then induced with 100 ng/mL LPS for 18-24 hrs.Cytokines in the media were measured according to MesoScale protocol.The negative control wells were treated with DMSO. Compound activity ismeasured as a percentage of LPS-induced activity.

FIG. 4 represents Anti-CD3-induced IL-2 secretion in PBMCs. 1 μg/mLanti-CD3 (OKT-3) antibody in PBS coated onto 96-well plates overnight at4° C. Approximately, 550,000 PBMCs were added to each well, followed byaddition of DMSO only (control) or Compound 1. Induction was measuredafter 24 hrs as fold difference from the DMSO stimulated control.

FIG. 5A represents a Western Blot from Jurkat cells treated with Control(DMSO only), or the indicated concentration of Compound 1. Cells werelysed using RIPA Buffer (Pierce) and a Western Blot was performed usinganti-casein kinase 1 alpha, (CK1-α) and anti-β-actin antibodies. FIG. 5Brepresents a Western Blot from Jurkat cells treated with Control (DMSOonly), or the indicated concentration of Compound 1, 2, 3, or 4. Cellswere lysed using RIPA Buffer (Pierce) and a Western Blot was performedusing anti-ikaros and anti-β-actin antibodies.

DETAILED DESCRIPTION

Some embodiments provide a compound of Formula (I), or apharmaceutically acceptable salt thereof:

In some embodiments, Q₁ can be CH₂, O, NR₂, S, or a bond. In someembodiments, when Q₁ is a bond, then m is not 0. In some embodiments, Q₂can be CH₂ or a bond. In some embodiments, when Q₂ can be a bond, Q₁ canbe a bond or CH₂.

In some embodiments, X can be CH₂ or C═O. In some embodiments, X can beCH₂. In some embodiments, X can be C═O.

In some embodiments, X₁ can be hydrogen, deuterium, methyl, or fluoro.

In some embodiments, X₁ can be hydrogen. In other embodiments, X₁ can befluoro. In still other embodiments, X₁ can be methyl. In someembodiments, X₁ can be deuterium.

In some embodiments, Ring B can be

wherein Y₁ is N or CR_(3A); Y₂ is N or CR_(3B); Y₃ is N or CR_(3C); Y₄is N or CR_(3D); Y₅ is N or CR_(3E). In some embodiments, Ring B can beselected from:

In some embodiments, Ring B is a phenyl group. In other embodiments,Ring B is a pyridyl group, such as a 2-pyridyl, 3-pyridyl, or 4-pyridylgroup.

In some embodiments, m can be 0, 1, 2, or 3. In some embodiments, mis 1. In some embodiments, m is 2. In some embodiments, m is 3.

In some embodiments, each R₁ can independently be deuterium, hydroxyl,halogen, nitro, a substituted or unsubstituted amino, a substituted orunsubstituted C₁-C₆ alkoxy, a substituted or unsubstituted C₁-C₆ alkyl,a substituted or unsubstituted C₂-C₆ alkenyl, a substituted orunsubstituted C₃-C₈ cycloalkyl, a substituted or unsubstituted 3 to 10membered heterocyclyl, a substituted or unsubstituted C₆-C₁₀ aryl, asubstituted or unsubstituted 5 to 10 membered heteroaryl, or L-Y. Insome embodiments, R₁ can be deuterium. In some embodiments, R₁ can behydroxyl. In some embodiments, R₁ can be halogen, for example, fluoro,chloro, or bromo. In some embodiments, R₁ can be nitro. In someembodiments, R₁ can be a substituted amino, for example, a (C₁-C₆alkyl)amino, a (3 to 10 membered heterocyclyl)amino or a (C₆-C₁₀aryl)amino. In some embodiments, R₁ can be an unsubstituted amino. Insome embodiments, R₁ can be a substituted C₁-C₆ alkyl which is anunsubstituted C₁-C₆ haloalkyl, for example, halomethyl, haloethyl,halo-n-propyl, haloisopropyl, halo-n-butyl, haloisobutyl,halo-sec-butyl, halo-t-butyl, halopentyl (straight-chained or branched),or halohexyl (straight-chained or branched). In some embodiments, R₁ canbe an unsubstituted C₁-C₆ fluoroalkyl. In some embodiments, R₁ can be anunsubstituted C₁-C₆ chloroalkyl. In some embodiments, R₁ can be anunsubstituted C₁-C₆ haloalkyl including both fluorine and chlorine. Insome embodiments, R₁ can be a substituted or unsubstituted C₁-C₆ alkoxy,for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, t-butoxy, pentoxy (straight-chained or branched),or hexoxy (straight-chained or branched). In some embodiments, R₁ can bean unsubstituted C₁-C₆ alkoxy, for example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy(straight-chained or branched), or hexoxy (straight-chained orbranched). In some embodiments, R₁ can be a substituted or unsubstitutedC₁-C₆ alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, pentyl (straight-chained or branched), orhexyl (straight-chained or branched). In some embodiments, R₁ can be anunsubstituted C₁-C₆ alkyl, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl(straight-chained or branched), or hexyl (straight-chained or branched).In some embodiments, R₁ can be a substituted or unsubstituted C₂-C₆alkenyl, for example, methylene, ethylene, n-propylene, isopropylene,n-butylene, isobutylene, sec-butylene, t-butylene, pentylene(straight-chained or branched), or hexylene (straight-chained orbranched). In some embodiments, R₁ can be an unsubstituted C₂-C₆alkenyl, for example, methylene, ethylene, n-propylene, isopropylene,n-butylene, isobutylene, sec-butylene, t-butylene, pentylene(straight-chained or branched), or hexylene (straight-chained orbranched). In some embodiments, R₁ can be a substituted or unsubstitutedC₃-C₈ cycloalkyl, for example, a C₃-C₈ monocyclic cycloalkyl or a C₆-C₈bridged, fused, or spiro bicyclic cycloalkyl. In some embodiments, R₁can be an unsubstituted C₃-C₈ C₈ cycloalkyl, for example, a C₃-C₈monocyclic cycloalkyl or a C₆-C₈ bridged, fused, or spiro bicycliccycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, octahydropentalene, decahydronaphthalene,bicyclo[4.2.0]octane, and bicyclo[3.1.1]heptane. In some embodiments, R₁can be a substituted or unsubstituted 3 to 10 membered heterocyclyl, forexample, a 3 to 8 membered monocyclic heterocyclyl, a 6 to 8 memberedbridged, fused, or spiro bicyclic heterocyclyl, or a 3 to 8 memberednitrogen-containing heterocyclyl. In some embodiments, R₁ can be anunsubstituted 3 to 10 membered heterocyclyl, for example, a 3 to 8membered monocyclic heterocyclyl, a 6 to 8 membered bridged, fused, orspiro bicyclic heterocyclyl, or a 3 to 8 membered nitrogen-containingheterocyclyl. In some embodiments, R₁ can be a substituted orunsubstituted C₆-C₁₀ aryl, for example, a phenyl or naphthyl. In someembodiments, R₁ can be an unsubstituted C₆-C₁₀ aryl such as phenyl ornaphthyl. In some embodiments, R₁ can be a substituted or unsubstituted5 to 10 membered heteroaryl, for example, a 5 membered heteroaryl, a 6membered heteroaryl, a 10 membered heteroaryl, or a 5 to 10 memberedheteroaryl with one or two nitrogen atoms. In some embodiments, R₁ canbe an unsubstituted 5 to 10 membered heteroaryl, for example, a 5membered heteroaryl, a 6 membered heteroaryl, a 10 membered heteroaryl,or a 5 to 10 membered heteroaryl with one or two nitrogen atoms. In someembodiments, R₁ can be L-Y, for example:

where “*” represents the point of connection of the L-Y moiety to therest of the molecule. In some embodiments, when R₁ can be L-Y, none ofR_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be L-Y.

In some embodiments, R₂ can be Hydrogen, deuterium, a substituted orunsubstituted C₁-C₆ alkyl, a substituted or unsubstituted C₂-C₆ alkenyl,acyl, or —(SO₂)—C₁-C₆ alkyl. In some embodiments, R₂ can be hydrogen. Insome embodiments, R₂ can be deuterium. In some embodiments, R₂ can be asubstituted or unsubstituted C₁-C₆, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl(straight-chained or branched), or hexyl (straight-chained or branched).In some embodiments, R₂ can be an unsubstituted C₁-C₆, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,t-butyl, pentyl (straight-chained or branched), or hexyl(straight-chained or branched). In some embodiments, R₂ can be asubstituted or unsubstituted C₂-C₆ alkenyl, for example, methylene,ethylene, n-propylene, isopropylene, n-butylene, isobutylene,sec-butylene, t-butylene, pentylene (straight-chained or branched), orhexylene (straight-chained or branched). In some embodiments, R₂ can bean unsubstituted C₂-C₆ alkenyl, for example, methylene, ethylene,n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene,t-butylene, pentylene (straight-chained or branched), or hexylene(straight-chained or branched). In some embodiments, R₂ can be acyl, forexample, a C₁-C₆ alkyl carbonyl such as acetyl (ethan-1-one),propan-1-one, or 3-methylbutan-1-one. In some embodiments, R₂ can be—(SO₂)—C₁-C₆ alkyl, for example, —(SO₂)-methyl, —(SO₂)-ethyl,—(SO₂)-n-propyl, —(SO₂)-isopropyl, —(SO₂)-n-butyl, —(SO₂)-isobutyl,—(SO₂)-sec-butyl, —(SO₂)-t-butyl, —(SO₂)-pentyl (straight-chained orbranched), or —(SO₂)-hexyl (straight-chained or branched).

In some embodiments, n can be 1, 2, or 3. In some embodiments, n can be1 or 2. In some embodiments, n can be 1. In some embodiments, n can be2.

In some embodiments, each of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be independently Hydrogen, deuterium, hydroxyl, halogen, nitro, asubstituted or unsubstituted amino, a substituted or unsubstituted C₁-C₆alkoxy, a substituted or unsubstituted C₁-C₆ alkyl, a substituted orunsubstituted C₂-C₆ alkenyl, a substituted or unsubstituted C₃-C₈cycloalkyl, a substituted or unsubstituted 3 to 10 memberedheterocyclyl, a substituted or unsubstituted alkoxyalkyl, a substitutedor unsubstituted cycloalkylalkyl, a substituted or unsubstitutedheterocyclylalkyl, a substituted or unsubstituted aralkyl, a substitutedor unsubstituted heteroaralkyl, or L-Y. In some embodiments, one or moreof R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be hydrogen. In someembodiments, one or more of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be deuterium. In some embodiments, one or more of R_(3A), R_(3B),R_(3C), R_(3D), and R_(3E) can be hydroxyl. In some embodiments, one ormore of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be halogen, forexample, fluoro, chloro, or bromo. In some embodiments, one or more ofR_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be nitro. In someembodiments, one or more of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be a substituted amino, for example, a (C₁-C₆ alkyl)amino, a (3 to10 membered heterocyclyl)amino or a (C₆-C₁₀ aryl)amino. In someembodiments, one or more of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be an unsubstituted amino. In some embodiments, one or more ofR_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be a substituted C₁-C₆alkyl which is an unsubstituted C₁-C₆ haloalkyl, for example,halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl,haloisobutyl, halo-sec-butyl, halo-t-butyl, halopentyl (straight-chainedor branched), or halohexyl (straight-chained or branched). In someembodiments, one or more of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be an unsubstituted C₁-C₆ fluoroalkyl. In some embodiments, one ormore of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be anunsubstituted C₁-C₆ chloroalkyl. In some embodiments, one or more ofR_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be an unsubstituted C₁-C₆haloalkyl including both fluorine and chlorine. In some embodiments, oneor more of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be asubstituted or unsubstituted C₁-C₆ alkoxy, for example, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy,pentoxy (straight-chained or branched), or hexoxy (straight-chained orbranched). In some embodiments, one or more of R_(3A), R_(3B), R_(3C),R_(3D), and R_(3E) can be an unsubstituted C₁-C₆ alkoxy, for example,methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,t-butoxy, pentoxy (straight-chained or branched), or hexoxy(straight-chained or branched). In some embodiments, one or more ofR_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be a substituted orunsubstituted C₁-C₆ alkyl, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl(straight-chained or branched), or hexyl (straight-chained or branched).In some embodiments, one or more of R_(3A), R_(3B), R_(3C), R_(3D), andR_(3E) can be an unsubstituted C₁-C₆ alkyl, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl(straight-chained or branched), or hexyl (straight-chained or branched).In some embodiments, one or more of R_(3A), R_(3B), R_(3C), R_(3D), andR_(3E) can be a substituted or unsubstituted C₂-C₆ alkenyl, for example,methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene,sec-butylene, t-butylene, pentylene (straight-chained or branched), orhexylene (straight-chained or branched). In some embodiments, one ormore of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be anunsubstituted C₂-C₆ alkenyl, for example, methylene, ethylene,n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene,t-butylene, pentylene (straight-chained or branched), or hexylene(straight-chained or branched). In some embodiments, one or more ofR_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be a substituted orunsubstituted C₃-C₈ cycloalkyl, for example, a C₃-C₈ monocycliccycloalkyl or a C₆-C₈ bridged, fused, or spiro bicyclic cycloalkyl. Insome embodiments, one or more of R_(3A), R_(3B), R_(3C), R_(3D), andR_(3E) can be an unsubstituted C₃-C₈ cycloalkyl, for example, a C₃-C₈monocyclic cycloalkyl or a C₆-C₈ bridged, fused, or spiro bicycliccycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, octahydropentalene, decahydronaphthalene,bicyclo[4.2.0]octane, and bicyclo[3.1.1]heptane. In some embodiments,one or more of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be asubstituted or unsubstituted 3 to 10 membered heterocyclyl, for example,a 3 to 8 membered monocyclic heterocyclyl, a 6 to 8 membered bridged,fused, or spiro bicyclic heterocyclyl, or a 3 to 8 memberednitrogen-containing heterocyclyl. In some embodiments, one or more ofR_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be an unsubstituted 3 to10 membered heterocyclyl, for example, a 3 to 8 membered monocyclicheterocyclyl, a 6 to 8 membered bridged, fused, or spiro bicyclicheterocyclyl, or a 3 to 8 membered nitrogen-containing heterocyclyl. Insome embodiments, one or more of R_(3A), R_(3B), R_(3C), R_(3D), andR_(3E) can be a substituted or unsubstituted alkoxyalkyl, for example, aC₁-C₄ alkoxy, as described herein and a C₁-C₄ alkyl, as describedherein. In some embodiments, one or more of R_(3A), R_(3B), R_(3C),R_(3D), and R_(3E) can be an unsubstituted alkoxyalkyl, for example, aC₁-C₄ alkoxy, as described herein and a C₁-C₄ alkyl, as describedherein, such as methoxymethyl, ethoxymethyl, or ethoxypropyl. In someembodiments, one or more of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be a substituted or unsubstituted cycloalkylalkyl, for example, aC₃-C₈ monocyclic cycloalkyl or a C₆-C₈ bridged, fused, or spiro bicycliccycloalkyl and a C₁-C₆ alkyl, as described herein. In some embodiments,one or more of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be anunsubstituted cycloalkylalkyl, for example, a C₃-C₈ monocycliccycloalkyl or a C₆-C₈ bridged, fused, or spiro bicyclic cycloalkyl and aC₁-C₆ alkyl, as described herein, such as cyclopropylmethyl,cyclobutylmethyl, cyclopentylethyl, or cyclohexylethyl. In someembodiments, one or more of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be a substituted or unsubstituted heterocyclylalkyl, for example, a3 to 8 membered monocyclic heterocyclyl, a 6 to 8 membered bridged,fused, or spiro bicyclic heterocyclyl, or a 3 to 8 memberednitrogen-containing heterocyclyl, and a C₁-C₆ alkyl, as describedherein. In some embodiments, one or more of R_(3A), R_(3B), R_(3C),R_(3D), and R_(3E) can be an unsubstituted heterocyclylalkyl, forexample, a 3 to 8 membered monocyclic heterocyclyl, a 6 to 8 memberedbridged, fused, or spiro bicyclic heterocyclyl, or a 3 to 8 memberednitrogen-containing heterocyclyl, and a C₁-C₆ alkyl, as describedherein, such as pyrrolidinylmethyl, piperidinylmethyl,piperazinylmethyl, or morpholinomethyl. In some embodiments, one or moreof R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be a substituted orunsubstituted aralkyl, for example, a C₆-C₁₀ aryl such as phenyl ornaphthyl and a C₁-C₆ alkyl, as described herein. In some embodiments,one or more of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be anunsubstituted aralkyl, for example, a C₆-C₁₀ aryl such as phenyl ornaphthyl and a C₁-C₆ alkyl, as described herein, such as benzyl orphenethyl. In some embodiments, one or more of R_(3A), R_(3B), R_(3C),R_(3D), and R_(3E) can be a substituted or unsubstituted heteroaralkyl,for example, a 5 membered heteroaryl, a 6 membered heteroaryl, a 10membered heteroaryl, or a 5 to 10 membered heteroaryl with one or twonitrogen atoms, and a C₁-C₆ alkyl, as described herein. In someembodiments, one or more of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be an unsubstituted heteroaralkyl, for example, a 5 memberedheteroaryl, a 6 membered heteroaryl, a 10 membered heteroaryl, or a 5 to10 membered heteroaryl with one or two nitrogen atoms, and a C₁-C₆alkyl, as described herein, such as pyridinylmethyl, pyrimidinylmethyl,or imidazolomethyl. In some embodiments, one of R_(3A), R_(3B), R_(3C),R_(3D), and R_(3E) can be L-Y, for example:

where “*” represents the point of connection of the L-Y moiety to therest of the molecule.

In some embodiments, when any one of R_(3A), R_(3B), R_(3C), R_(3D), andR_(3E) can be L-Y, R₁ cannot be L-Y. In some embodiments, R_(3A) cannotbe hydrogen. In some embodiments, R_(3B) cannot be hydrogen. In someembodiments, R_(3C) cannot be hydrogen. In some embodiments, R_(3D)cannot be hydrogen. In some embodiments, R_(3E) cannot be hydrogen.

In some embodiments, L can be —Z₁—(R₄)_(t)—Z₂—; —Z₁—(R₄—O—R₄)_(t)—Z₂—;—Z₁(R₄—NH—R₄)_(t)—Z₂—; —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂—; or—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂—. In some embodiments, L can be—Z₁—(R₄—O—R₄)_(t)—Z₂—. In other embodiments, L can be—Z₁(R₄—NH—R₄)_(t)—Z₂—. In still other embodiments, L can be—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂—. In some embodiments, L can beZ₁—(R₄—(CONH)—R₄)_(t)—Z₂—. In other embodiments, L can be—Z₁—(R₄)_(t)—Z₂—. In still other embodiments, L can be—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂—.

In some embodiments, each R₄ can be independently an unsubstituted C₁-C₆alkylene, for example, methylene, ethylene, n-propylene, isopropylene,n-butylene, isobutylene, sec-butylene, t-butylene, pentylene(straight-chained or branched), or hexylene (straight-chained orbranched). In some embodiments, each R₄ group is the same. In someembodiments, each R₄ group is different.

In some embodiments, t can be 1, 2, 3, 4, 5, or 6. In some embodiments,t can be 1. In some embodiments, t can be 2. In some embodiments, t canbe 3. In some embodiments, t can be 4. In some embodiments, t can be 5.In some embodiments, t can be 6.

Some embodiments of L are shown in Table A, below.

TABLE A L Z₁ Z₂ t —Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂NH(CO)— —NH— 1—Z₁—(R₄—O—R₄)_(t)—Z₂— —NH— —NH— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —O— —NH— 1—Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂— —NH— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —NH(CO)— —NH— 1—Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂NH— —NH— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —NHCH₂— —NH—1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂NH(CO)— —O— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —NH— —O—1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —O— —O— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂— —O— 1—Z₁—(R₄—O—R₄)_(t)—Z₂— —NH(CO)— —O— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂NH— —O— 1—Z₁—(R₄—O—R₄)_(t)—Z₂— —NHCH₂— —O— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂NH(CO)——CH₂— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —NH— —CH₂— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —O——CH₂— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂— —CH₂— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂——NH(CO)— —CH₂— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂NH— —CH₂— 1—Z₁—(R₄—O—R₄)_(t)—Z₂— —NHCH₂— —CH₂— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂NH(CO)——NH(CO)— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —NH— —NH(CO)— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂——O— —NH(CO)— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂— —NH(CO)— 1—Z₁—(R₄—O—R₄)_(t)—Z₂— —NH(CO)— —NH(CO)— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂NH——NH(CO)— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —NHCH₂— —NH(CO)— 1—Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂NH(CO)— —(CO)NH— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —NH——(CO)NH— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —O— —(CO)NH— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂——CH₂— —(CO)NH— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —NH(CO)— —(CO)NH— 1—Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂NH— —(CO)NH— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —NHCH₂——(CO)NH— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂NH(CO)— —CH₂NH— 1—Z₁—(R₄—O—R₄)_(t)—Z₂— —NH— —CH₂NH— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —O— —CH₂NH— 1—Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂— —CH₂NH— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —NH(CO)——CH₂NH— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂NH— —CH₂NH— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂——NHCH₂— —CH₂NH— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂NH(CO)— —NHCH₂— 1—Z₁—(R₄—O—R₄)_(t)—Z₂— —NH— —NHCH₂— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —O— —NHCH₂— 1—Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂— —NHCH₂— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —NH(CO)——NHCH₂— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂— —CH₂NH— —NHCH₂— 1 —Z₁—(R₄—O—R₄)_(t)—Z₂——NHCH₂— —NHCH₂— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂NH(CO)— —NH— 1—Z₁—(R₄—NH—R₄)_(t)—Z₂— —NH— —NH— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —O— —NH— 1—Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂— —NH— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —NH(CO)— —NH—1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂NH— —NH— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —NHCH₂——NH— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂NH(CO)— —O— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂——NH— —O— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —O— —O— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂——O— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —NH(CO)— —O— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂——CH₂NH— —O— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —NHCH₂— —O— 1—Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂NH(CO)— —CH₂— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —NH——CH₂— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —O— —CH₂— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂——CH₂— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —NH(CO)— —CH₂— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂——CH₂NH— —CH₂— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —NHCH₂— —CH₂— 1—Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂NH(CO)— —NH(CO)— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂——NH— —NH(CO)— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —O— —NH(CO)— 1—Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂— —NH(CO)— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —NH(CO)——NH(CO)— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂NH— —NH(CO)— 1—Z₁—(R₄—NH—R₄)_(t)—Z₂— —NHCH₂— —NH(CO)— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂——CH₂NH(CO)— —(CO)NH— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —NH— —(CO)NH— 1—Z₁—(R₄—NH—R₄)_(t)—Z₂— —O— —(CO)NH— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂——(CO)NH— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —NH(CO)— —(CO)NH— 1—Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂NH— —(CO)NH— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —NHCH₂——(CO)NH— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂NH(CO)— —CH₂NH— 1—Z₁—(R₄—NH—R₄)_(t)—Z₂— —NH— —CH₂NH— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —O— —CH₂NH—1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂— —CH₂NH— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —NH(CO)——CH₂NH— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂NH— —CH₂NH— 1—Z₁—(R₄—NH—R₄)_(t)—Z₂— —NHCH₂— —CH₂NH— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂——CH₂NH(CO)— —NHCH₂— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —NH— —NHCH₂— 1—Z₁—(R₄—NH—R₄)_(t)—Z₂— —O— —NHCH₂— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂——NHCH₂— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —NH(CO)— —NHCH₂— 1—Z₁—(R₄—NH—R₄)_(t)—Z₂— —CH₂NH— —NHCH₂— 1 —Z₁—(R₄—NH—R₄)_(t)—Z₂— —NHCH₂——NHCH₂— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂NH(CO)— —NH— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NH— —NH— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —O——NH— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂— —NH— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NH(CO)— —NH— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂——CH₂NH— —NH— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NHCH₂— —NH— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂NH(CO)— —O— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂——NH— —O— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —O— —O— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂— —O— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂——NH(CO)— —O— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂NH— —O— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NHCH₂— —O— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂——CH₂NH(CO)— —CH₂— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NH— —CH₂— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —O— —CH₂— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂——CH₂— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NH(CO)— —CH₂— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂NH— —CH₂— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂——NHCH₂— —CH₂— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂NH(CO)— —NH(CO)— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NH— —NH(CO)— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂——O— —NH(CO)— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂— —NH(CO)— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NH(CO)— —NH(CO)— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂NH— —NH(CO)— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂——NHCH₂— —NH(CO)— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂NH(CO)— —(CO)NH— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NH— —(CO)NH— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂——O— —(CO)NH— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂— —(CO)NH— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NH(CO)— —(CO)NH— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂NH— —(CO)NH— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂——NHCH₂— —(CO)NH— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂NH(CO)— —CH₂NH— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NH— —CH₂NH— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —O——CH₂NH— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂— —CH₂NH— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NH(CO)— —CH₂NH— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂——CH₂NH— —CH₂NH— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NHCH₂— —CH₂NH— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂NH(CO)— —NHCH₂— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NH— —NHCH₂— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —O——NHCH₂— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —CH₂— —NHCH₂— 1—Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NH(CO)— —NHCH₂— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂——CH₂NH— —NHCH₂— 1 —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂— —NHCH₂— —NHCH₂— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —NH— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂——NH— —NH— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —O— —NH— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂— —NH— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂——NH(CO)— —NH— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂NH— —NH— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NHCH₂— —NH— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂——CH₂NH(CO)— —O— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NH— —O— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —O— —O— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂——O— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NH(CO)— —O— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂NH— —O— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂——NHCH₂— —O— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —CH₂— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NH— —CH₂— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —O——CH₂— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂— —CH₂— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NH(CO)— —CH₂— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂——CH₂NH— —CH₂— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NHCH₂— —CH₂— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —NH(CO)— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NH— —NH(CO)— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂——O— —NH(CO)— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂— —NH(CO)— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NH(CO)— —NH(CO)— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂NH— —NH(CO)— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂——NHCH₂— —NH(CO)— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —(CO)NH— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NH— —(CO)NH— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂——O— —(CO)NH— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂— —(CO)NH— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NH(CO)— —(CO)NH— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂NH— —(CO)NH— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂——NHCH₂— —(CO)NH— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —CH₂NH— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NH— —CH₂NH— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —O——CH₂NH— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂— —CH₂NH— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NH(CO)— —CH₂NH— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂——CH₂NH— —CH₂NH— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NHCH₂— —CH₂NH— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —NHCH₂— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NH— —NHCH₂— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —O——NHCH₂— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —CH₂— —NHCH₂— 1—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NH(CO)— —NHCH₂— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂——CH₂NH— —NHCH₂— 1 —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂— —NHCH₂— —NHCH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH— —NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —O— —NH— 1 —Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂——CH₂— —NH— 1 —Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH(CO)— —NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH— —NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NHCH₂— —NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —O— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH— —O— 1 —Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂——O— —O— 1 —Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂— —O— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH(CO)— —O— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH— —O— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NHCH₂— —O— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —CH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH— —CH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —O— —CH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂— —CH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH(CO)— —CH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH— —CH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NHCH₂— —CH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —NH(CO)— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH— —NH(CO)— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —O— —NH(CO)— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂— —NH(CO)— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH(CO)— —NH(CO)— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH— —NH(CO)— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NHCH₂— —NH(CO)— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —(CO)NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH— —(CO)NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —O— —(CO)NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂— —(CO)NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH(CO)— —(CO)NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH— —(CO)NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NHCH₂— —(CO)NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —CH₂NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH— —CH₂NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —O— —CH₂NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂— —CH₂NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH(CO)— —CH₂NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH— —CH₂NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NHCH₂— —CH₂NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —NHCH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH— —NHCH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —O— —NHCH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂— —NHCH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH(CO)— —NHCH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH— —NHCH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NHCH₂— —NHCH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH— —NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —O— —NH— 1 —Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂——CH₂— —NH— 1 —Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH(CO)— —NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH— —NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NHCH₂— —NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —O— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH— —O— 1 —Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂——O— —O— 1 —Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂— —O— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH(CO)— —O— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH— —O— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NHCH₂— —O— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —CH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH— —CH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —O— —CH₂— 1 —Z₁—(R₄—(NHC(O)NH)—R₄)t—Z₂——CH₂— —CH₂— 1 —Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH(CO)— —CH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH— —CH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NHCH₂— —CH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —NH(CO)— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH— —NH(CO)— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —O— —NH(CO)— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂— —NH(CO)— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH(CO)— —NH(CO)— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH— —NH(CO)— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NHCH₂— —NH(CO)— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —(CO)NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH— —(CO)NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —O— —(CO)NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂— —(CO)NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH(CO)— —(CO)NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH— —(CO)NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NHCH₂— —(CO)NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —CH₂NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH— —CH₂NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —O— —CH₂NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂— —CH₂NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH(CO)— —CH₂NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH— —CH₂NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NHCH₂— —CH₂NH— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH(CO)— —NHCH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH— —NHCH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —O— —NHCH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂— —NHCH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NH(CO)— —NHCH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —CH₂NH— —NHCH₂— 1—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂— —NHCH₂— —NHCH₂— 1

In some embodiments of Table A, each R₄ can independently be a C₁-C₄alkylene, for example, methylene, ethylene, n-propylene, isopropylene,n-butylene, isobutylene, or sec-butylene. In some embodiments of TableA, each R₄ is methylene. In some embodiments of Table A, each R₄ isethylene. In some embodiments of Table A, each R₄ is n-propylene. Insome embodiments of Table A, each R₄ is n-butylene. In some embodimentsof Table A, each R₄ can be the same. In some embodiments of Table A,each R₄ can be different. For example, one R₄ can be methylene and theother R₄ can be ethylene; one R₄ can be methylene and the other R₄ canbe n-propylene; one R₄ can be methylene and the other R₄ can ben-butylene; one R₄ can be ethylene and the other R₄ can be n-propylene;or one R₄ can be ethylene and the other R₄ can be n-butylene.

In some embodiments, Y can be

wherein Y can be derivatized to attach to L. As used herein, the phrase“Y is derivatized to attach to L” is used as would be understood by onehaving ordinary skill in the art. For example, when Y is derivatized toattached to L, Y can be:

wherein * represents the point of attachment to the L group.

In some embodiments, at least one of Y₁, Y₂, Y₃, Y₄, and Y₅ is carbon(e.g., CR_(3A), CR_(3B), CR_(3C), CR_(3D), and/or CR_(3E)). In someembodiments, one of Y₁, Y₂, Y₃, Y₄, and Y₅ is carbon. In someembodiments, two of Y₁, Y₂, Y₃, Y₄, and Y₅ are carbon. In someembodiments, three of Y₁, Y₂, Y₃, Y₄, and Y₅ are carbon. In someembodiments, four of Y₁, Y₂, Y₃, Y₄, and Y₅ are carbon. In someembodiments, all five of Y₁, Y₂, Y₃, Y₄, and Y₅ are carbon.

In some embodiments, when Q₁ is CH₂, then one or more of R_(3A), R_(3B),R_(3C), R_(3D), and R_(3E) cannot be hydrogen. In some embodiments, whenQ₁ is a bond, then one or more of R_(3A), R_(3B), R_(3C), R_(3D), andR_(3E) cannot be hydrogen. In some embodiments, when R₁ is L-Y, none ofR_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be L-Y. In someembodiments, when Q₁ is a bond, X₁ is hydrogen or methyl, and Q₂ is CH₂;then one of R₁, R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) is L-Y. Insome embodiments, when Q₂ can be a bond, Q₁ can be a bond or CH₂.

In some embodiments, each R₁ can be independently halogen (for example,fluoro, chloro, or bromo), a substituted or unsubstituted amino (forexample, —NH₂, dimethylamino, diethylamino, isopropylethylamino,phenylamino, or benzylamino), an unsubstituted C₁-C₆ haloalkyl (forexample, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃, or —CH₂CH₂CF₃), a substituted orunsubstituted C₁-C₆ alkoxy (for example, (for example, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy,pentoxy (straight-chained or branched), or hexoxy (straight-chained orbranched)), or a substituted or unsubstituted C₁-C₆ alkyl (for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,t-butyl, pentyl (straight-chained or branched), or hexyl(straight-chained or branched)). In some embodiments, each R₁ can beindependently halogen (for example, fluoro, chloro, or bromo), anunsubstituted amino, an unsubstituted C₁-C₆ haloalkyl, an unsubstitutedC₁-C₆ alkoxy (for example, (for example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy(straight-chained or branched), or hexoxy (straight-chained orbranched)), or unsubstituted C₁-C₆ alkyl (for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl(straight-chained or branched), or hexyl (straight-chained orbranched)).

In some embodiments, each R₁ can be independently fluoro, chloro, —NH₂,—NH(CH₃), —N(CH₃)₂, —CF₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —CH₃, —CH₂CH₃ or—CH(CH₃)₂.

In some embodiments, Ring B can be selected from:

In some embodiments, each of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be independently hydrogen, deuterium, hydroxyl, halogen (forexample, fluoro, chloro, or bromo), nitro, a substituted orunsubstituted amino (for example, —NH₂, dimethylamino, diethylamino,isopropylethylamino, phenylamino, or benzylamino), a substituted orunsubstituted C₁-C₆ alkoxy (for example, (for example, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy,pentoxy (straight-chained or branched), or hexoxy (straight-chained orbranched)), or a substituted or unsubstituted C₁-C₆ alkyl (for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,t-butyl, pentyl (straight-chained or branched), or hexyl(straight-chained or branched)), a substituted or unsubstituted C₂-C₆alkenyl (for example, ethylene, n-propylene, isopropylene, n-butylene,isobutylene, sec-butylene, t-butylene, pentylene (straight-chained orbranched), or hexylene (straight-chained or branched)), a substituted orunsubstituted C₃-C₈ cycloalkyl (for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl), a substituted orunsubstituted 3 to 10 membered heterocyclyl (for example a 3 to 8membered monocyclic heterocyclyl containing one or two heteroatomsselected from oxygen and nitrogen, or a 6 to 8 membered bicyclicheterocyclyl containing one or two heteroatoms selected from oxygen andnitrogen), a substituted or unsubstituted alkoxyalkyl (for example,methoxymethyl, ethoxyethyl, or methoxy-t-butyl), a substituted orunsubstituted cycloalkylalkyl (for example, a C₃-C₈ cycloalkyl groupsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,or cyclooctyl, connected to the rest of the compound via a C₁-C₃ alkylgroup such as methyl, ethyl, n-propyl, or isopropyl), a substituted orunsubstituted heterocyclylalkyl (for example, for example a 3 to 8membered monocyclic heterocyclyl containing one or two heteroatomsselected from oxygen and nitrogen, connected to the rest of the compoundvia a C₁-C₃ alkyl group such as methyl, ethyl, n-propyl, or isopropyl),a substituted or unsubstituted aralkyl (for example, phenyl or naphthyl,connected to the rest of the compound via a C₁-C₃ alkyl group such asmethyl, ethyl, n-propyl, or isopropyl), or a substituted orunsubstituted heteroaralkyl, for example, a five, six, or ten memberedheteroaryl group containing either one oxygen, one nitrogen, one oxygenand one nitrogen, two nitrogens, or three nitrogens, connected to therest of the compound via a C₁-C₃ alkyl group such as methyl, ethyl,n-propyl, or isopropyl).

In some embodiments, each of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be independently Hydrogen, deuterium, hydroxyl, halogen (forexample, fluoro, chloro, or bromo), nitro, a substituted orunsubstituted amino (for example, —NH₂, dimethylamino, diethylamino,isopropylethylamino, phenylamino, or benzylamino), an unsubstitutedC₁-C₆ haloalkyl (for example, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃, or—CH₂CH₂CF₃), an unsubstituted C₁-C₆ alkoxy (for example, methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,t-butoxy, pentoxy (straight-chained or branched), or hexoxy(straight-chained or branched)), or unsubstituted C₁-C₆ alkyl (forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, pentyl (straight-chained or branched), or hexyl(straight-chained or branched)), an unsubstituted C₂-C₆ alkenyl (forexample, ethylene, n-propylene, isopropylene, n-butylene, isobutylene,sec-butylene, t-butylene, pentylene (straight-chained or branched), orhexylene (straight-chained or branched)), an unsubstituted C₃-C₈cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, or cyclooctyl), an unsubstituted 3 to 10membered heterocyclyl (for example a 3 to 8 membered monocyclicheterocyclyl containing one or two heteroatoms selected from oxygen andnitrogen, or a 6 to 8 membered bicyclic heterocyclyl containing one ortwo heteroatoms selected from oxygen and nitrogen), an unsubstitutedalkoxyalkyl (for example, methoxymethyl, ethoxyethyl, ormethoxy-t-butyl), an unsubstituted cycloalkylalkyl (for example, a C₃-C₈cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, or cyclooctyl, connected to the rest of thecompound via a C₁-C₃ alkyl group such as methyl, ethyl, n-propyl, orisopropyl), an unsubstituted heterocyclylalkyl (for example, for examplea 3 to 8 membered monocyclic heterocyclyl containing one or twoheteroatoms selected from oxygen and nitrogen, connected to the rest ofthe compound via a C₁-C₃ alkyl group such as methyl, ethyl, n-propyl, orisopropyl), an unsubstituted aralkyl (for example, phenyl or naphthyl,connected to the rest of the compound via a C₁-C₃ alkyl group such asmethyl, ethyl, n-propyl, or isopropyl), or unsubstituted heteroaralkyl(for example, a five, six, or ten membered heteroaryl group containingeither one oxygen, one nitrogen, one oxygen and one nitrogen, twonitrogens, or three nitrogens, connected to the rest of the compound viaa C₁-C₃ alkyl group such as methyl, ethyl, n-propyl, or isopropyl).

In some embodiments, each of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be independently hydrogen, halogen (for example, fluoro, chloro, orbromo), an unsubstituted C₁-C₆ haloalkyl (for example, —CF₃, —CHF₂,—CH₂F, —CH₂CF₃, or —CH₂CH₂CF₃), an unsubstituted C₁-C₆ alkoxy (forexample, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy, t-butoxy, pentoxy (straight-chained or branched), or hexoxy(straight-chained or branched)), an unsubstituted C₁-C₆ alkyl (forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, pentyl (straight-chained or branched), or hexyl(straight-chained or branched)), an unsubstituted 3 to 10 memberedheterocyclyl (for example a 3 to 8 membered monocyclic heterocyclylcontaining one or two heteroatoms selected from oxygen and nitrogen, ora 6 to 8 membered bicyclic heterocyclyl containing one or twoheteroatoms selected from oxygen and nitrogen), or an unsubstituted 3 to10 membered heterocyclylalkyl (for example a 3 to 8 membered monocyclicheterocyclyl containing one or two heteroatoms selected from oxygen andnitrogen, or a 6 to 8 membered bicyclic heterocyclyl containing one ortwo heteroatoms selected from oxygen and nitrogen, connected to the restof the compound by a methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, pentyl (straight-chained or branched), orhexyl (straight-chained or branched) group).

In some embodiments, one of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be halogen (for example, fluoro, chloro, or bromo), an unsubstitutedC₁-C₆ haloalkyl, an unsubstituted C₁-C₆ alkoxy (for example, methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,t-butoxy, pentoxy (straight-chained or branched), or hexoxy(straight-chained or branched)), an unsubstituted C₁-C₆ alkyl (forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, pentyl (straight-chained or branched), or hexyl(straight-chained or branched)), an unsubstituted 3 to 10 memberedheterocyclyl (for example a 3 to 8 membered monocyclic heterocyclylcontaining one or two heteroatoms selected from oxygen and nitrogen, ora 6 to 8 membered bicyclic heterocyclyl containing one or twoheteroatoms selected from oxygen and nitrogen), or an unsubstituted 3 to10 membered heterocyclylalkyl (for example a 3 to 8 membered monocyclicheterocyclyl containing one or two heteroatoms selected from oxygen andnitrogen, or a 6 to 8 membered bicyclic heterocyclyl containing one ortwo heteroatoms selected from oxygen and nitrogen, connected to the restof the compound by a methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, pentyl (straight-chained or branched), orhexyl (straight-chained or branched) group) and the other of R_(3A),R_(3B), R_(3C), R_(3D), and R_(3E) are hydrogen.

In some embodiments, one of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be fluoro, chloro, —CF₃, —OCH₃, an unsubstituted C₁-C₆ alkyl (forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, pentyl (straight-chained or branched), or hexyl(straight-chained or branched)), an unsubstituted 3 to 10 memberedheterocyclyl (for example a 3 to 8 membered monocyclic heterocyclylcontaining one or two heteroatoms selected from oxygen and nitrogen, ora 6 to 8 membered bicyclic heterocyclyl containing one or twoheteroatoms selected from oxygen and nitrogen), or an unsubstituted 3 to10 membered heterocyclylalkyl (for example a 3 to 8 membered monocyclicheterocyclyl containing one or two heteroatoms selected from oxygen andnitrogen, or a 6 to 8 membered bicyclic heterocyclyl containing one ortwo heteroatoms selected from oxygen and nitrogen, connected to the restof the compound by a methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, pentyl (straight-chained or branched), orhexyl (straight-chained or branched) group) and the other of R_(3A),R_(3B), R_(3C), R_(3D), and R_(3E) are hydrogen.

In some embodiments, one of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E)can be selected from:

and the other of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can behydrogen.

In some embodiments, one R₁ can be L-Y. In some embodiments, one ofR_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) can be L-Y. In someembodiments, Y₃ can be C-L-Y.

In some embodiments, L can be —Z₁—(R₄—O—R₄)_(t)—Z₂—. In someembodiments, L can be —Z₁(R₄—NH—R₄)_(t)—Z₂—. In some embodiments, L canbe Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂—. In some embodiments, L can be—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂—. In other embodiments, L can be—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂—. In some embodiments of this paragraph, tis 1. In some embodiments of this paragraph, t is 2.

In some embodiments, Z₁ can be —NH—. In some embodiments, Z₁ can be —O—.In some embodiments, Z₁ can be —CH₂—. In some embodiments, Z₁ can be—NH(CO)—. In some embodiments, Z₁ can be —CH₂NH—. In some embodiments,Z₁ can be —NHCH₂—. In some embodiments, Z₂ can be —NH—. In someembodiments, Z₂ can be —O—. In some embodiments, Z₂ can be —CH₂—. Insome embodiments, Z₂ can be —NH(CO)—. In some embodiments, Z₂ can be—(CO)NH—. In some embodiments, Z₂ can be —CH₂NH—. In some embodiments,Z₂ can be —NHCH₂—. In some embodiments of this paragraph, Z₁ and Z₂ arethe same. In some embodiments of this paragraph, Z₁ and Z₂ aredifferent. In some embodiments of this paragraph, when Z₁ can be —NH—,Z₂ can be —NH—. In some embodiments of this paragraph, when Z₁ can be—O—, Z₂ can be —O—. In some embodiments of this paragraph, when Z₁ canbe —CH₂—, Z₂ can be —CH₂—. In some embodiments of this paragraph, whenZ₁ can be —NH(CO)—, Z₂ can be —NH(CO)—. In some embodiments of thisparagraph, when Z₁ can be —CH₂NH—, Z₂ can be —CH₂NH—. In someembodiments of this paragraph, when Z₁ can be —CH₂NH(CO)—, Z₂ can be—NH—. In some embodiments of this paragraph, when Z₁ can be —CH₂NH(CO)—,Z₂ can be —O—. In some embodiments of this paragraph, when Z₁ can be—CH₂NH(CO)—, Z₂ can be —CH₂—. In some embodiments of this paragraph,when Z₁ can be —CH₂NH(CO)—, Z₂ can be —NH(CO)—. In some embodiments ofthis paragraph, when Z₁ can be —CH₂NH(CO)—, Z₂ can be —CH₂NH—.

In some embodiments, each R₄ can be independently an unsubstituted C₁-C₄alkylene, for example, methylene, ethylene, n-propylene, isopropylene,n-butylene, sec-butylene, or t-butylene. In some embodiments, each R₄can be independently an unsubstituted C₁-C₂ alkylene, such as methyleneor ethylene.

In some embodiments, t can be 1. In some embodiments, t can be 2. Insome embodiments, t can be 3. In some embodiments, t can be 4. In someembodiments, t can be 5. In some embodiments, t can be 6.

In some embodiments, the compound of Formula (I) is selected from:

or a pharmaceutically acceptable salt of any of the foregoing.

Some embodiments of compounds of Formula (I) are shown in Table B,below.

TABLE B X X₁ Q₁ Q₂ Y₁ Y₂ Y₃ Y₄ Y₅ C═O H CH₂ CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃bond C═O H O CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond C═O H NR₂ CH₂ or CR₃ CR₃CR₃ CR₃ CR₃ bond C═O H S CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond C═O H a bondCH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond C═O methyl CH₂ CH₂ or CR₃ CR₃ CR₃ CR₃CR₃ bond C═O methyl O CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond C═O methyl NR₂ CH₂or CR₃ CR₃ CR₃ CR₃ CR₃ bond C═O methyl S CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bondC═O methyl a bond CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond C═O D CH₂ CH₂ or CR₃CR₃ CR₃ CR₃ CR₃ bond C═O D O CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond C═O D NR₂CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond C═O D S CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bondC═O D a bond CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond C═O fluoro CH₂ CH₂ or CR₃CR₃ CR₃ CR₃ CR₃ bond C═O fluoro O CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond C═Ofluoro NR₂ CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond C═O fluoro S CH₂ or CR₃ CR₃CR₃ CR₃ CR₃ bond C═O fluoro a bond CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond CH₂ HCH₂ CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond CH₂ H O CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃bond CH₂ H NR₂ CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond CH₂ H S CH₂ or CR₃ CR₃CR₃ CR₃ CR₃ bond CH₂ H a bond CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond CH₂ methylCH₂ CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond CH₂ methyl O CH₂ or CR₃ CR₃ CR₃ CR₃CR₃ bond CH₂ methyl NR₂ CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond CH₂ methyl S CH₂or CR₃ CR₃ CR₃ CR₃ CR₃ bond CH₂ methyl a bond CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃bond CH₂ D CH₂ CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond CH₂ D O CH₂ or CR₃ CR₃CR₃ CR₃ CR₃ bond CH₂ D NR₂ CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond CH₂ D S CH₂or CR₃ CR₃ CR₃ CR₃ CR₃ bond CH₂ D a bond CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bondCH₂ fluoro CH₂ CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond CH₂ fluoro O CH₂ or CR₃CR₃ CR₃ CR₃ CR₃ bond CH₂ fluoro NR₂ CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond CH₂fluoro S CH₂ or CR₃ CR₃ CR₃ CR₃ CR₃ bond CH₂ fluoro a bond CH₂ or CR₃CR₃ CR₃ CR₃ CR₃ bond C═O H CH₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond C═O H O CH₂or N CR₃ CR₃ CR₃ CR₃ bond C═O H NR₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond C═O HS CH₂ or N CR₃ CR₃ CR₃ CR₃ bond C═O H a bond CH₂ or N CR₃ CR₃ CR₃ CR₃bond C═O methyl CH₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond C═O methyl O CH₂ or NCR₃ CR₃ CR₃ CR₃ bond C═O methyl NR₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond C═Omethyl S CH₂ or N CR₃ CR₃ CR₃ CR₃ bond C═O methyl a bond CH₂ or N CR₃CR₃ CR₃ CR₃ bond C═O D CH₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond C═O D O CH₂ orN CR₃ CR₃ CR₃ CR₃ bond C═O D NR₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond C═O D SCH₂ or N CR₃ CR₃ CR₃ CR₃ bond C═O D a bond CH₂ or N CR₃ CR₃ CR₃ CR₃ bondC═O fluoro CH₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond C═O fluoro O CH₂ or N CR₃CR₃ CR₃ CR₃ bond C═O fluoro NR₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond C═O fluoroS CH₂ or N CR₃ CR₃ CR₃ CR₃ bond C═O fluoro a bond CH₂ or N CR₃ CR₃ CR₃CR₃ bond CH₂ H CH₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond CH₂ H O CH₂ or N CR₃CR₃ CR₃ CR₃ bond CH₂ H NR₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond CH₂ H S CH₂ orN CR₃ CR₃ CR₃ CR₃ bond CH₂ H a bond CH₂ or N CR₃ CR₃ CR₃ CR₃ bond CH₂methyl CH₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond CH₂ methyl O CH₂ or N CR₃ CR₃CR₃ CR₃ bond CH₂ methyl NR₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond CH₂ methyl SCH₂ or N CR₃ CR₃ CR₃ CR₃ bond CH₂ methyl a bond CH₂ or N CR₃ CR₃ CR₃ CR₃bond CH₂ D CH₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond CH₂ D O CH₂ or N CR₃ CR₃CR₃ CR₃ bond CH₂ D NR₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond CH₂ D S CH₂ or NCR₃ CR₃ CR₃ CR₃ bond CH₂ D a bond CH₂ or N CR₃ CR₃ CR₃ CR₃ bond CH₂fluoro CH₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond CH₂ fluoro O CH₂ or N CR₃ CR₃CR₃ CR₃ bond CH₂ fluoro NR₂ CH₂ or N CR₃ CR₃ CR₃ CR₃ bond CH₂ fluoro SCH₂ or N CR₃ CR₃ CR₃ CR₃ bond CH₂ fluoro a bond CH₂ or N CR₃ CR₃ CR₃ CR₃bond C═O H CH₂ CH₂ or CR₃ N CR₃ CR₃ CR₃ bond C═O H O CH₂ or CR₃ N CR₃CR₃ CR₃ bond C═O H NR₂ CH₂ or CR₃ N CR₃ CR₃ CR₃ bond C═O H S CH₂ or CR₃N CR₃ CR₃ CR₃ bond C═O H a bond CH₂ or CR₃ N CR₃ CR₃ CR₃ bond C═O methylCH₂ CH₂ or CR₃ N CR₃ CR₃ CR₃ bond C═O methyl O CH₂ or CR₃ N CR₃ CR₃ CR₃bond C═O methyl NR₂ CH₂ or CR₃ N CR₃ CR₃ CR₃ bond C═O methyl S CH₂ orCR₃ N CR₃ CR₃ CR₃ bond C═O methyl a bond CH₂ or CR₃ N CR₃ CR₃ CR₃ bondC═O D CH₂ CH₂ or CR₃ N CR₃ CR₃ CR₃ bond C═O D O CH₂ or CR₃ N CR₃ CR₃ CR₃bond C═O D NR₂ CH₂ or CR₃ N CR₃ CR₃ CR₃ bond C═O D S CH₂ or CR₃ N CR₃CR₃ CR₃ bond C═O D a bond CH₂ or CR₃ N CR₃ CR₃ CR₃ bond C═O fluoro CH₂CH₂ or CR₃ N CR₃ CR₃ CR₃ bond C═O fluoro O CH₂ or CR₃ N CR₃ CR₃ CR₃ bondC═O fluoro NR₂ CH₂ or CR₃ N CR₃ CR₃ CR₃ bond C═O fluoro S CH₂ or CR₃ NCR₃ CR₃ CR₃ bond C═O fluoro a bond CH₂ or CR₃ N CR₃ CR₃ CR₃ bond CH₂ HCH₂ CH₂ or CR₃ N CR₃ CR₃ CR₃ bond CH₂ H O CH₂ or CR₃ N CR₃ CR₃ CR₃ bondCH₂ H NR₂ CH₂ or CR₃ N CR₃ CR₃ CR₃ bond CH₂ H S CH₂ or CR₃ N CR₃ CR₃ CR₃bond CH₂ H a bond CH₂ or CR₃ N CR₃ CR₃ CR₃ bond CH₂ methyl CH₂ CH₂ orCR₃ N CR₃ CR₃ CR₃ bond CH₂ methyl O CH₂ or CR₃ N CR₃ CR₃ CR₃ bond CH₂methyl NR₂ CH₂ or CR₃ N CR₃ CR₃ CR₃ bond CH₂ methyl S CH₂ or CR₃ N CR₃CR₃ CR₃ bond CH₂ methyl a bond CH₂ or CR₃ N CR₃ CR₃ CR₃ bond CH₂ D CH₂CH₂ or CR₃ N CR₃ CR₃ CR₃ bond CH₂ D O CH₂ or CR₃ N CR₃ CR₃ CR₃ bond CH₂D NR₂ CH₂ or CR₃ N CR₃ CR₃ CR₃ bond CH₂ D S CH₂ or CR₃ N CR₃ CR₃ CR₃bond CH₂ D a bond CH₂ or CR₃ N CR₃ CR₃ CR₃ bond CH₂ fluoro CH₂ CH₂ orCR₃ N CR₃ CR₃ CR₃ bond CH₂ fluoro O CH₂ or CR₃ N CR₃ CR₃ CR₃ bond CH₂fluoro NR₂ CH₂ or CR₃ N CR₃ CR₃ CR₃ bond CH₂ fluoro S CH₂ or CR₃ N CR₃CR₃ CR₃ bond CH₂ fluoro a bond CH₂ or CR₃ N CR₃ CR₃ CR₃ bond C═O H CH₂CH₂ or CR₃ CR₃ N CR₃ CR₃ bond C═O H O CH₂ or CR₃ CR₃ N CR₃ CR₃ bond C═OH NR₂ CH₂ or CR₃ CR₃ N CR₃ CR₃ bond C═O H S CH₂ or CR₃ CR₃ N CR₃ CR₃bond C═O H a bond CH₂ or CR₃ CR₃ N CR₃ CR₃ bond C═O methyl CH₂ CH₂ orCR₃ CR₃ N CR₃ CR₃ bond C═O methyl O CH₂ or CR₃ CR₃ N CR₃ CR₃ bond C═Omethyl NR₂ CH₂ or CR₃ CR₃ N CR₃ CR₃ bond C═O methyl S CH₂ or CR₃ CR₃ NCR₃ CR₃ bond C═O methyl a bond CH₂ or CR₃ CR₃ N CR₃ CR₃ bond C═O D CH₂CH₂ or CR₃ CR₃ N CR₃ CR₃ bond C═O D O CH₂ or CR₃ CR₃ N CR₃ CR₃ bond C═OD NR₂ CH₂ or CR₃ CR₃ N CR₃ CR₃ bond C═O D S CH₂ or CR₃ CR₃ N CR₃ CR₃bond C═O D a bond CH₂ or CR₃ CR₃ N CR₃ CR₃ bond C═O fluoro CH₂ CH₂ orCR₃ CR₃ N CR₃ CR₃ bond C═O fluoro O CH₂ or CR₃ CR₃ N CR₃ CR₃ bond C═Ofluoro NR₂ CH₂ or CR₃ CR₃ N CR₃ CR₃ bond C═O fluoro S CH₂ or CR₃ CR₃ NCR₃ CR₃ bond C═O fluoro a bond CH₂ or CR₃ CR₃ N CR₃ CR₃ bond CH₂ H CH₂CH₂ or CR₃ CR₃ N CR₃ CR₃ bond CH₂ H O CH₂ or CR₃ CR₃ N CR₃ CR₃ bond CH₂H NR₂ CH₂ or CR₃ CR₃ N CR₃ CR₃ bond CH₂ H S CH₂ or CR₃ CR₃ N CR₃ CR₃bond CH₂ H a bond CH₂ or CR₃ CR₃ N CR₃ CR₃ bond CH₂ methyl CH₂ CH₂ orCR₃ CR₃ N CR₃ CR₃ bond CH₂ methyl O CH₂ or CR₃ CR₃ N CR₃ CR₃ bond CH₂methyl NR₂ CH₂ or CR₃ CR₃ N CR₃ CR₃ bond CH₂ methyl S CH₂ or CR₃ CR₃ NCR₃ CR₃ bond CH₂ methyl a bond CH₂ or CR₃ CR₃ N CR₃ CR₃ bond CH₂ D CH₂CH₂ or CR₃ CR₃ N CR₃ CR₃ bond CH₂ D O CH₂ or CR₃ CR₃ N CR₃ CR₃ bond CH₂D NR₂ CH₂ or CR₃ CR₃ N CR₃ CR₃ bond CH₂ D S CH₂ or CR₃ CR₃ N CR₃ CR₃bond CH₂ D a bond CH₂ or CR₃ CR₃ N CR₃ CR₃ bond CH₂ fluoro CH₂ CH₂ orCR₃ CR₃ N CR₃ CR₃ bond CH₂ fluoro O CH₂ or CR₃ CR₃ N CR₃ CR₃ bond CH₂fluoro NR₂ CH₂ or CR₃ CR₃ N CR₃ CR₃ bond CH₂ fluoro S CH₂ or CR₃ CR₃ NCR₃ CR₃ bond CH₂ fluoro a bond CH₂ or CR₃ CR₃ N CR₃ CR₃ bond C═O H CH₂CH₂ or N N CR₃ CR₃ CR₃ bond C═O H O CH₂ or N N CR₃ CR₃ CR₃ bond C═O HNR₂ CH₂ or N N CR₃ CR₃ CR₃ bond C═O H S CH₂ or N N CR₃ CR₃ CR₃ bond C═OH a bond CH₂ or N N CR₃ CR₃ CR₃ bond C═O methyl CH₂ CH₂ or N N CR₃ CR₃CR₃ bond C═O methyl O CH₂ or N N CR₃ CR₃ CR₃ bond C═O methyl NR₂ CH₂ orN N CR₃ CR₃ CR₃ bond C═O methyl S CH₂ or N N CR₃ CR₃ CR₃ bond C═O methyla bond CH₂ or N N CR₃ CR₃ CR₃ bond C═O D CH₂ CH₂ or N N CR₃ CR₃ CR₃ bondC═O D O CH₂ or N N CR₃ CR₃ CR₃ bond C═O D NR₂ CH₂ or N N CR₃ CR₃ CR₃bond C═O D S CH₂ or N N CR₃ CR₃ CR₃ bond C═O D a bond CH₂ or N N CR₃ CR₃CR₃ bond C═O fluoro CH₂ CH₂ or N N CR₃ CR₃ CR₃ bond C═O fluoro O CH₂ orN N CR₃ CR₃ CR₃ bond C═O fluoro NR₂ CH₂ or N N CR₃ CR₃ CR₃ bond C═Ofluoro S CH₂ or N N CR₃ CR₃ CR₃ bond C═O fluoro a bond CH₂ or N N CR₃CR₃ CR₃ bond CH₂ H CH₂ CH₂ or N N CR₃ CR₃ CR₃ bond CH₂ H O CH₂ or N NCR₃ CR₃ CR₃ bond CH₂ H NR₂ CH₂ or N N CR₃ CR₃ CR₃ bond CH₂ H S CH₂ or NN CR₃ CR₃ CR₃ bond CH₂ H a bond CH₂ or N N CR₃ CR₃ CR₃ bond CH₂ methylCH₂ CH₂ or N N CR₃ CR₃ CR₃ bond CH₂ methyl O CH₂ or N N CR₃ CR₃ CR₃ bondCH₂ methyl NR₂ CH₂ or N N CR₃ CR₃ CR₃ bond CH₂ methyl S CH₂ or N N CR₃CR₃ CR₃ bond CH₂ methyl a bond CH₂ or N N CR₃ CR₃ CR₃ bond CH₂ D CH₂ CH₂or N N CR₃ CR₃ CR₃ bond CH₂ D O CH₂ or N N CR₃ CR₃ CR₃ bond CH₂ D NR₂CH₂ or N N CR₃ CR₃ CR₃ bond CH₂ D S CH₂ or N N CR₃ CR₃ CR₃ bond CH₂ D abond CH₂ or N N CR₃ CR₃ CR₃ bond CH₂ fluoro CH₂ CH₂ or N N CR₃ CR₃ CR₃bond CH₂ fluoro O CH₂ or N N CR₃ CR₃ CR₃ bond CH₂ fluoro NR₂ CH₂ or N NCR₃ CR₃ CR₃ bond CH₂ fluoro S CH₂ or N N CR₃ CR₃ CR₃ bond CH₂ fluoro abond CH₂ or N N CR₃ CR₃ CR₃ bond C═O H CH₂ CH₂ or N CR₃ CR₃ CR₃ N bondC═O H O CH₂ or N CR₃ CR₃ CR₃ N bond C═O H NR₂ CH₂ or N CR₃ CR₃ CR₃ Nbond C═O H S CH₂ or N CR₃ CR₃ CR₃ N bond C═O H a bond CH₂ or N CR₃ CR₃CR₃ N bond C═O methyl CH₂ CH₂ or N CR₃ CR₃ CR₃ N bond C═O methyl O CH₂or N CR₃ CR₃ CR₃ N bond C═O methyl NR₂ CH₂ or N CR₃ CR₃ CR₃ N bond C═Omethyl S CH₂ or N CR₃ CR₃ CR₃ N bond C═O methyl a bond CH₂ or N CR₃ CR₃CR₃ N bond C═O D CH₂ CH₂ or N CR₃ CR₃ CR₃ N bond C═O D O CH₂ or N CR₃CR₃ CR₃ N bond C═O D NR₂ CH₂ or N CR₃ CR₃ CR₃ N bond C═O D S CH₂ or NCR₃ CR₃ CR₃ N bond C═O D a bond CH₂ or N CR₃ CR₃ CR₃ N bond C═O fluoroCH₂ CH₂ or N CR₃ CR₃ CR₃ N bond C═O fluoro O CH₂ or N CR₃ CR₃ CR₃ N bondC═O fluoro NR₂ CH₂ or N CR₃ CR₃ CR₃ N bond C═O fluoro S CH₂ or N CR₃ CR₃CR₃ N bond C═O fluoro a bond CH₂ or N CR₃ CR₃ CR₃ N bond CH₂ H CH₂ CH₂or N CR₃ CR₃ CR₃ N bond CH₂ H O CH₂ or N CR₃ CR₃ CR₃ N bond CH₂ H NR₂CH₂ or N CR₃ CR₃ CR₃ N bond CH₂ H S CH₂ or N CR₃ CR₃ CR₃ N bond CH₂ H abond CH₂ or N CR₃ CR₃ CR₃ N bond CH₂ methyl CH₂ CH₂ or N CR₃ CR₃ CR₃ Nbond CH₂ methyl O CH₂ or N CR₃ CR₃ CR₃ N bond CH₂ methyl NR₂ CH₂ or NCR₃ CR₃ CR₃ N bond CH₂ methyl S CH₂ or N CR₃ CR₃ CR₃ N bond CH₂ methyl abond CH₂ or N CR₃ CR₃ CR₃ N bond CH₂ D CH₂ CH₂ or N CR₃ CR₃ CR₃ N bondCH₂ D O CH₂ or N CR₃ CR₃ CR₃ N bond CH₂ D NR₂ CH₂ or N CR₃ CR₃ CR₃ Nbond CH₂ D S CH₂ or N CR₃ CR₃ CR₃ N bond CH₂ D a bond CH₂ or N CR₃ CR₃CR₃ N bond CH₂ fluoro CH₂ CH₂ or N CR₃ CR₃ CR₃ N bond CH₂ fluoro O CH₂or N CR₃ CR₃ CR₃ N bond CH₂ fluoro NR₂ CH₂ or N CR₃ CR₃ CR₃ N bond CH₂fluoro S CH₂ or N CR₃ CR₃ CR₃ N bond CH₂ fluoro a bond CH₂ or N CR₃ CR₃CR₃ N bond C═O H CH₂ CH₂ or CR₃ N CR₃ N CR₃ bond C═O H O CH₂ or CR₃ NCR₃ N CR₃ bond C═O H NR₂ CH₂ or CR₃ N CR₃ N CR₃ bond C═O H S CH₂ or CR₃N CR₃ N CR₃ bond C═O H a bond CH₂ or CR₃ N CR₃ N CR₃ bond C═O methyl CH₂CH₂ or CR₃ N CR₃ N CR₃ bond C═O methyl O CH₂ or CR₃ N CR₃ N CR₃ bond C═Omethyl NR₂ CH₂ or CR₃ N CR₃ N CR₃ bond C═O methyl S CH₂ or CR₃ N CR₃ NCR₃ bond C═O methyl a bond CH₂ or CR₃ N CR₃ N CR₃ bond C═O D CH₂ CH₂ orCR₃ N CR₃ N CR₃ bond C═O D O CH₂ or CR₃ N CR₃ N CR₃ bond C═O D NR₂ CH₂or CR₃ N CR₃ N CR₃ bond C═O D S CH₂ or CR₃ N CR₃ N CR₃ bond C═O D a bondCH₂ or CR₃ N CR₃ N CR₃ bond C═O fluoro CH₂ CH₂ or CR₃ N CR₃ N CR₃ bondC═O fluoro O CH₂ or CR₃ N CR₃ N CR₃ bond C═O fluoro NR₂ CH₂ or CR₃ N CR₃N CR₃ bond C═O fluoro S CH₂ or CR₃ N CR₃ N CR₃ bond C═O fluoro a bondCH₂ or CR₃ N CR₃ N CR₃ bond CH₂ H CH₂ CH₂ or CR₃ N CR₃ N CR₃ bond CH₂ HO CH₂ or CR₃ N CR₃ N CR₃ bond CH₂ H NR₂ CH₂ or CR₃ N CR₃ N CR₃ bond CH₂H S CH₂ or CR₃ N CR₃ N CR₃ bond CH₂ H a bond CH₂ or CR₃ N CR₃ N CR₃ bondCH₂ methyl CH₂ CH₂ or CR₃ N CR₃ N CR₃ bond CH₂ methyl O CH₂ or CR₃ N CR₃N CR₃ bond CH₂ methyl NR₂ CH₂ or CR₃ N CR₃ N CR₃ bond CH₂ methyl S CH₂or CR₃ N CR₃ N CR₃ bond CH₂ methyl a bond CH₂ or CR₃ N CR₃ N CR₃ bondCH₂ D CH₂ CH₂ or CR₃ N CR₃ N CR₃ bond CH₂ D O CH₂ or CR₃ N CR₃ N CR₃bond CH₂ D NR₂ CH₂ or CR₃ N CR₃ N CR₃ bond CH₂ D S CH₂ or CR₃ N CR₃ NCR₃ bond CH₂ D a bond CH₂ or CR₃ N CR₃ N CR₃ bond CH₂ fluoro CH₂ CH₂ orCR₃ N CR₃ N CR₃ bond CH₂ fluoro O CH₂ or CR₃ N CR₃ N CR₃ bond CH₂ fluoroNR₂ CH₂ or CR₃ N CR₃ N CR₃ bond CH₂ fluoro S CH₂ or CR₃ N CR₃ N CR₃ bondCH₂ fluoro a bond CH₂ or CR₃ N CR₃ N CR₃ bond C═O H CH₂ CH₂ or N CR₃ NCR₃ CR₃ bond C═O H O CH₂ or N CR₃ N CR₃ CR₃ bond C═O H NR₂ CH₂ or N CR₃N CR₃ CR₃ bond C═O H S CH₂ or N CR₃ N CR₃ CR₃ bond C═O H a bond CH₂ or NCR₃ N CR₃ CR₃ bond C═O methyl CH₂ CH₂ or N CR₃ N CR₃ CR₃ bond C═O methylO CH₂ or N CR₃ N CR₃ CR₃ bond C═O methyl NR₂ CH₂ or N CR₃ N CR₃ CR₃ bondC═O methyl S CH₂ or N CR₃ N CR₃ CR₃ bond C═O methyl a bond CH₂ or N CR₃N CR₃ CR₃ bond C═O D CH₂ CH₂ or N CR₃ N CR₃ CR₃ bond C═O D O CH₂ or NCR₃ N CR₃ CR₃ bond C═O D NR₂ CH₂ or N CR₃ N CR₃ CR₃ bond C═O D S CH₂ orN CR₃ N CR₃ CR₃ bond C═O D a bond CH₂ or N CR₃ N CR₃ CR₃ bond C═O fluoroCH₂ CH₂ or N CR₃ N CR₃ CR₃ bond C═O fluoro O CH₂ or N CR₃ N CR₃ CR₃ bondC═O fluoro NR₂ CH₂ or N CR₃ N CR₃ CR₃ bond C═O fluoro S CH₂ or N CR₃ NCR₃ CR₃ bond C═O fluoro a bond CH₂ or N CR₃ N CR₃ CR₃ bond CH₂ H CH₂ CH₂or N CR₃ N CR₃ CR₃ bond CH₂ H O CH₂ or N CR₃ N CR₃ CR₃ bond CH₂ H NR₂CH₂ or N CR₃ N CR₃ CR₃ bond CH₂ H S CH₂ or N CR₃ N CR₃ CR₃ bond CH₂ H abond CH₂ or N CR₃ N CR₃ CR₃ bond CH₂ methyl CH₂ CH₂ or N CR₃ N CR₃ CR₃bond CH₂ methyl O CH₂ or N CR₃ N CR₃ CR₃ bond CH₂ methyl NR₂ CH₂ or NCR₃ N CR₃ CR₃ bond CH₂ methyl S CH₂ or N CR₃ N CR₃ CR₃ bond CH₂ methyl abond CH₂ or N CR₃ N CR₃ CR₃ bond CH₂ D CH₂ CH₂ or N CR₃ N CR₃ CR₃ bondCH₂ D O CH₂ or N CR₃ N CR₃ CR₃ bond CH₂ D NR₂ CH₂ or N CR₃ N CR₃ CR₃bond CH₂ D S CH₂ or N CR₃ N CR₃ CR₃ bond CH₂ D a bond CH₂ or N CR₃ N CR₃CR₃ bond CH₂ fluoro CH₂ CH₂ or N CR₃ N CR₃ CR₃ bond CH₂ fluoro O CH₂ orN CR₃ N CR₃ CR₃ bond CH₂ fluoro NR₂ CH₂ or N CR₃ N CR₃ CR₃ bond CH₂fluoro S CH₂ or N CR₃ N CR₃ CR₃ bond CH₂ fluoro a bond CH₂ or N CR₃ NCR₃ CR₃ bond C═O H CH₂ CH₂ or CR₃ CR₃ N CR₃ N bond C═O H O CH₂ or CR₃CR₃ N CR₃ N bond C═O H NR₂ CH₂ or CR₃ CR₃ N CR₃ N bond C═O H S CH₂ orCR₃ CR₃ N CR₃ N bond C═O H a bond CH₂ or CR₃ CR₃ N CR₃ N bond C═O methylCH₂ CH₂ or CR₃ CR₃ N CR₃ N bond C═O methyl O CH₂ or CR₃ CR₃ N CR₃ N bondC═O methyl NR₂ CH₂ or CR₃ CR₃ N CR₃ N bond C═O methyl S CH₂ or CR₃ CR₃ NCR₃ N bond C═O methyl a bond CH₂ or CR₃ CR₃ N CR₃ N bond C═O D CH₂ CH₂or CR₃ CR₃ N CR₃ N bond C═O D O CH₂ or CR₃ CR₃ N CR₃ N bond C═O D NR₂CH₂ or CR₃ CR₃ N CR₃ N bond C═O D S CH₂ or CR₃ CR₃ N CR₃ N bond C═O D abond CH₂ or CR₃ CR₃ N CR₃ N bond C═O fluoro CH₂ CH₂ or CR₃ CR₃ N CR₃ Nbond C═O fluoro O CH₂ or CR₃ CR₃ N CR₃ N bond C═O fluoro NR₂ CH₂ or CR₃CR₃ N CR₃ N bond C═O fluoro S CH₂ or CR₃ CR₃ N CR₃ N bond C═O fluoro abond CH₂ or CR₃ CR₃ N CR₃ N bond CH₂ H CH₂ CH₂ or CR₃ CR₃ N CR₃ N bondCH₂ H O CH₂ or CR₃ CR₃ N CR₃ N bond CH₂ H NR₂ CH₂ or CR₃ CR₃ N CR₃ Nbond CH₂ H S CH₂ or CR₃ CR₃ N CR₃ N bond CH₂ H a bond CH₂ or CR₃ CR₃ NCR₃ N bond CH₂ methyl CH₂ CH₂ or CR₃ CR₃ N CR₃ N bond CH₂ methyl O CH₂or CR₃ CR₃ N CR₃ N bond CH₂ methyl NR₂ CH₂ or CR₃ CR₃ N CR₃ N bond CH₂methyl S CH₂ or CR₃ CR₃ N CR₃ N bond CH₂ methyl a bond CH₂ or CR₃ CR₃ NCR₃ N bond CH₂ D CH₂ CH₂ or CR₃ CR₃ N CR₃ N bond CH₂ D O CH₂ or CR₃ CR₃N CR₃ N bond CH₂ D NR₂ CH₂ or CR₃ CR₃ N CR₃ N bond CH₂ D S CH₂ or CR₃CR₃ N CR₃ N bond CH₂ D a bond CH₂ or CR₃ CR₃ N CR₃ N bond CH₂ fluoro CH₂CH₂ or CR₃ CR₃ N CR₃ N bond CH₂ fluoro O CH₂ or CR₃ CR₃ N CR₃ N bond CH₂fluoro NR₂ CH₂ or CR₃ CR₃ N CR₃ N bond CH₂ fluoro S CH₂ or CR₃ CR₃ N CR₃N bond CH₂ fluoro a bond CH₂ or CR₃ CR₃ N CR₃ N bond

In some embodiments of Table B, R₂ can be hydrogen. In some embodimentsof Table B, R₂ can be a substituted or unsubstituted C₁-C₆ alkyl, forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, pentyl (straight-chained or branched), or hexyl(straight-chained or branched). In some embodiments of Table B, R₂ canbe an unsubstituted C₁-C₆ alkyl, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl(straight-chained or branched), or hexyl (straight-chained or branched).In some embodiments of Table B, R₂ can be acyl, for example,—(C═O)-methyl, —(C═O)-ethyl, —(C═O)-n-propyl, —(C═O)-isopropyl,—(C═O)-n-butyl, —(C═O)-isobutyl, —(C═O)-sec-butyl, —(C═O)-t-butyl,—(C═O)-pentyl (straight-chained or branched), or —(C═O)-hexyl(straight-chained or branched). In some embodiments of Table B, R₂ canbe —(SO₂)—C₁-C₆ alkyl, for example, —(SO₂)-methyl, —(SO₂)-ethyl,—(SO₂)-n-propyl, —(SO₂)-isopropyl, —(SO₂)-n-butyl, —(SO₂)-isobutyl,—(SO₂)-sec-butyl, —(SO₂)-t-butyl, —(SO₂)-pentyl (straight-chained orbranched), or —(SO₂)-hexyl (straight-chained or branched).

In some embodiments, a compound of Formula (I) is selected from:

In some embodiments of this paragraph, R₁ can be fluoro. In someembodiments of this paragraph, R₁ can be chloro. In some embodiments ofthis paragraph, R₁ can be hydroxyl. In some embodiments of thisparagraph, R₁ can be —NH₂. In some embodiments of this paragraph, R₁ canbe —CF₃, —CHF₂, or —CH₂F. In some embodiments of this paragraph, R₁ canbe an unsubstituted C₁-C₆ alkoxy, such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy(straight-chained or branched), or hexoxy (straight-chained orbranched). In some embodiments of this paragraph, R₁ can be anunsubstituted C₁-C₆ alkyl, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (straight-chained orbranched), or hexyl (straight-chained or branched). In some embodimentsof this paragraph, R₁ can be an unsubstituted C₃-C₈ cycloalkyl, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. In some embodiments of this paragraph, R₁ can be anunsubstituted 3 to 10 membered heterocyclyl, for example, a monocyclicheterocyclyl, a bridged heterocyclyl, or a fused heterocyclyl, includinggroups such as pyrrolidine, piperidine, piperazine, and morpholine. Insome embodiments of this paragraph, R_(3B) can be hydroxyl. In someembodiments of this paragraph, R_(3B) can be fluoro. In some embodimentsof this paragraph, R_(3B) can be chloro. In some embodiments of thisparagraph, R_(3B) can be a substituted or unsubstituted amino, forexample, —NH₂, dimethylamino, diethylamino, isopropylethylamino,phenylamino, or benzylamino. In some embodiments of this paragraph,R_(3B) can be —CF₃, —CHF₂, or —CH₂F. In some embodiments of thisparagraph, R_(3B) can be an unsubstituted C₁-C₆ alkoxy, such as methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,t-butoxy, pentoxy (straight-chained or branched), or hexoxy(straight-chained or branched). In some embodiments of this paragraph,R_(3B) can be an unsubstituted C₁-C₆ alkyl, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl(straight-chained or branched), or hexyl (straight-chained or branched).In some embodiments of this paragraph, R_(3B) can be an unsubstitutedC₃-C₈ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments of thisparagraph, R_(3C) can be a substituted or unsubstituted C₃-C₈cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. In some embodiments of this paragraph,R_(3C) can be an unsubstituted C₃-C₈ cycloalkyl, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Insome embodiments of this paragraph, R_(3C) can be a substituted orunsubstituted 3 to 10 membered heterocyclyl, for example, a monocyclicheterocyclyl, a bridged heterocyclyl, or a fused heterocyclyl, includinggroups such as pyrrolidine, piperidine, piperazine, and morpholine. Insome embodiments of this paragraph, R_(3C) can be an unsubstituted 3 to10 membered heterocyclyl, for example, a monocyclic heterocyclyl, abridged heterocyclyl, or a fused heterocyclyl, including groups such aspyrrolidine, piperidine, piperazine, and morpholine. In some embodimentsof this paragraph, R_(3C) can be a substituted or unsubstituted 5 to 10membered heteroaryl, for example, a 5 or 6 membered heteroarylcontaining at least one nitrogen, such as pyrrole, imidazole, oxazole,thiazole, pyridine, or pyrimidine. In some embodiments of thisparagraph, R_(3C) can be an unsubstituted 5 to 10 membered heteroaryl,for example, a 5 or 6 membered heteroaryl containing at least onenitrogen, such as pyrrole, imidazole, oxazole, thiazole, pyridine, orpyrimidine.

Compounds of Formula (I) can be provided in the form of pharmaceuticallyacceptable salts, solvates, or tautomers, thereof.

Some embodiments provide a pharmaceutical composition comprising acompound of Formula (I), or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable excipient. In some embodiments, thepharmaceutical composition also contains at least one pharmaceuticallyacceptable inactive ingredient. The pharmaceutical composition can beformulated for intravenous injection, subcutaneous injection, oraladministration, buccal administration, inhalation, nasal administration,topical administration, transdermal administration, ophthalmicadministration, or otic administration. The pharmaceutical compositioncan be in the form of a tablet, a pill, a capsule, a liquid, aninhalant, a nasal spray solution, a suppository, a suspension, a gel, acolloid, a dispersion, a solution, an emulsion, an ointment, a lotion,an eye drop, or an ear drop.

In some embodiments, the pharmaceutical composition is formulated as agel, salve, ointment, cream, emulsion, or paste for topical applicationto the skin.

Some embodiments provide a method of inhibiting the activity of acytokine, comprising contacting a cell with an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof.In some embodiments, the cytokine is selected from: IL-1β, IL-2, IL-6,and TNFα. In some embodiments, the cytokine is TNFα. In someembodiments, the cell is a cancer cell.

Some embodiments provide a method of inhibiting the activity of aiolos,comprising contacting a cell with an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof

Some embodiments provide a method of inhibiting the activity of ikaros,comprising contacting a cell with an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. In someembodiments, the cell is a cancer cell.

Some embodiments provide a method of inhibiting the activity of helios,comprising contacting a cell with an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. In someembodiments, the cell is a cancer cell.

Some embodiments provide a method of inhibiting the activity of CK-1α,comprising contacting a cell with an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. In someembodiments, the cell is a cancer cell.

In some embodiments, the cell is a small cell lung cancer cell, anon-small cell lung cancer cell, a breast cancer cell, a prostate cancercell, a head and neck cancer cell, a pancreatic cancer cell, a coloncancer cell, a rectal cancer cell, a teratoma cell, an ovarian cancercell, an endometrial cancer cell, a brain cancer cell, a retinoblastomacell, a leukemia cell, a skin cancer cell, a melanoma cell, a squamouscell carcinoma cell, a liposarcoma cell, a lymphoma cell, a multiplemyeloma cell, a testicular cancer cell, a liver cancer cell, anesophageal cancer cell, a kidney carcinoma cell, an astrogliosis cell, arelapsed/refractory multiple myeloma cell, or a neuroblastoma cell.

In some embodiments, inhibiting the activity of a protein can includedecreasing the activity of the protein by 20-50%, by 30-70%, by 40-90%,or any value in between. For example, inhibiting the activity of aprotein can include decreasing the activity of the protein by 10%, 15%,20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 99%, or any value in between.

Some embodiments provide a method of treating, ameliorating, orpreventing a disease, disorder, or condition associated with a proteinin a subject, the protein selected from a cytokine, aiolos, ikaros,helios, CK1α, and combinations of any of the foregoing; the methodcomprising administering a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition comprising a compound of Formula (I), ora pharmaceutically acceptable salt thereof, to the subject.

In some embodiments, the disease, disorder, or condition is a cancerselected from a hematological malignancy and a solid tumor In someembodiments, the disease, disorder, or condition is a cancer selectedfrom small cell lung cancer, non-small cell lung cancer, breast cancer,prostate cancer, head and neck cancer, pancreatic cancer, colon cancer,rectal cancer, teratoma, ovarian cancer, endometrial cancer, braincancer, retinoblastoma, leukemia, skin cancer, melanoma, squamous cellcarcinoma, liposarcoma, lymphoma, multiple myeloma, testicular cancer,liver cancer, esophageal cancer, kidney carcinoma, astrogliosis,relapsed/refractory multiple myeloma, and neuroblastoma.

In some embodiments, the disease, disorder, or condition is selectedfrom inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis,ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatorybowel diseases, Crohn's disease, ulcerative colitis, uveitis,inflammatory lung diseases, chronic obstructive pulmonary disease, andAlzheimer's disease. In some embodiments, the disease, disorder, orcondition is selected from fibromyalgia, rheumatoid arthritis,osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis,Crohn's disease, and ulcerative colitis.

In some embodiments, the protein is a cytokine. In some embodiments, thecytokine is selected from: IL-1β, IL-2, IL-6, and TNFα. In someembodiments, the subject is known to possess wild-type IL-1β, IL-2,IL-6, and TNFα. In some embodiments, the subject is known to overexpressone or more of IL-1β, IL-2, IL-6, and TNFα. In some embodiments, thesubject is known to possess a mutant form of IL-1β, IL-2, IL-6, and/orTNFα.

In some embodiments, the cytokine is TNFα. In some embodiments, thesubject is known to possess wild-type TNFα. In some embodiments, thesubject is known to overexpress TNFα. In some embodiments, the subjectis known to possess a mutant form of TNFα. In some embodiments, theprotein is aiolos. In some embodiments, the subject is known to possesswild-type aiolos. In some embodiments, the subject is known tooverexpress aiolos. In some embodiments, the subject is known to possessa mutant form of aiolos. In some embodiments, the protein is ikaros. Insome embodiments, the subject is known to possess wild-type ikaros. Insome embodiments, the subject is known to overexpress ikaros. In someembodiments, the subject is known to possess a mutant form of ikaros. Insome embodiments, the protein is helios. In some embodiments, thesubject is known to possess wild-type helios. In some embodiments, thesubject is known to overexpress helios. In some embodiments, the subjectis known to possess a mutant form of helios. In some embodiments, theprotein is CK1α. In some embodiments, the subject is known to possesswild-type CK1α. In some embodiments, the subject is known to overexpressCK1α. In some embodiments, the subject is known to possess a mutant formof CK1α.

Other objects, features, and advantages of the compounds, methods, andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise. As used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology are employed. The use of “or” or “and” means “and/or”unless stated otherwise. Furthermore, use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting. As used in this specification, whether in a transitionalphrase or in the body of the claim, the terms “comprise(s)” and“comprising” are to be interpreted as having an open-ended meaning. Thatis, the terms are to be interpreted synonymously with the phrases“having at least” or “including at least.” When used in the context of aprocess, the term “comprising” means that the process includes at leastthe recited steps, but may include additional steps. When used in thecontext of a compound, composition, or device, the term “comprising”means that the compound, composition, or device includes at least therecited features or components, but may also include additional featuresor components.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

The terms “co-administration” and similar terms as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation toadministration of the selected therapeutic agents to a single patient,and are intended to include treatment regimens in which the agents areadministered by the same or different route of administration or at thesame or different time.

The terms “effective amount” and “therapeutically effective amount” arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to asufficient amount of an agent or a compound being administered whichwill relieve to some extent one or more of the symptoms of the diseaseor condition being treated. The result can be reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic uses is the amount of the composition comprisinga compound as disclosed herein required to provide a clinicallysignificant decrease in disease symptoms. An appropriate “effective”amount in any individual case may be determined using techniques, suchas a dose escalation study. Where a drug has been approved by the U.S.Food and Drug Administration (FDA) or a counterpart foreign medicinesagency, a “therapeutically effective amount” optionally refers to thedosage approved by the FDA or its counterpart foreign agency fortreatment of the identified disease or condition.

As used herein, any “R” group(s) such as, without limitation, R₂, R₃,R₄, R₅, R₆, R₉, and R₁₀ represent substituents that can be attached tothe indicated atom. An R group may be substituted or unsubstituted. Iftwo “R” groups are described as being “taken together” the R groups andthe atoms they are attached to can form a cycloalkyl, aryl, heteroaryl,or heterocycle. For example, without limitation, if R² and R³, or R²,R³, or R⁴, and the atom to which it is attached, are indicated to be“taken together” or “joined together” it means that they are covalentlybonded to one another to form a ring:

Whenever a group is described as being “substituted” or “optionallysubstituted” that group may be unsubstituted or substituted with one ormore of the indicated substituents. Likewise, when a group is describedas being “unsubstituted or substituted” if substituted, the substituentmay be selected from one or more the indicated substituents. If nosubstituents are indicated, it is meant that the indicated or“substituted” group may be individually and independently substitutedwith one or more group(s) individually and independently selected fromalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, (heterocyclyl)alkyl, hydroxy, protectedhydroxyl, alkoxy, aryloxy, acyl, cyano, halogen, ester, nitro, silyl,haloalkyl, haloalkoxy, an unsubstituted amino, a substituted amino, andprotected derivatives thereof.

As used herein, “C_(a) to C_(b)” in which “a” and “b” are integers referto the number of carbon atoms in an alkyl, alkenyl or alkynyl group, orthe number of carbon atoms in the ring of a cycloalkyl, aryl, heteroarylor heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of thecycloalkyl, ring of the aryl, ring of the heteroaryl or ring of theheterocyclyl can contain from “a” to “b”, inclusive, carbon atoms. Thus,for example, a “C₁ to C₄ alkyl” group or a “C₁-C₄ alkyl” group refers toall alkyl groups having from 1 to 4 carbons, that is, CH₃—, CH₃CH₂—,CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and (CH₃)₃C—.Likewise, for example, a heterocyclyl group may contain from “a” to “b”,inclusive, total atoms, such as a 3 to 10-membered heterocyclyl group,which includes 3 to ten total atoms (carbon and heteroatoms). If no “a”and “b” are designated with regard to an alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl or heterocyclyl group, the broadest rangedescribed in these definitions is to be assumed.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms(whenever it appears herein, a numerical range such as “1 to 20” refersto each integer in the given range; e.g., “1 to 20 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 20 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 10 carbon atoms. The alkyl group could also be alower alkyl having 1 to 6 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁-C₄ alkyl” or similar designations. By way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from methyl,ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, andhexyls. The alkyl group may be substituted or unsubstituted.

As used herein, “alkenyl” refers to an alkyl group, as defined herein,that contains in the straight or branched hydrocarbon chain one or moredouble bonds. An alkenyl group may be unsubstituted or substituted.

As used herein, “alkynyl” refers to an alkyl group as defined herein,that contains in the straight or branched hydrocarbon chain one or moretriple bonds. An alkynyl group may be unsubstituted or substituted.

As used herein, “alkylene” refers to a straight-chained or branchedalkyl group forming bonds to connect molecular fragments via theirterminal carbon atoms. Examples include but are not limited to methylene(—CH₂—), ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), and butylene(—CH₂CH₂CH₂CH₂—). An alkylene group can be substituted by replacing oneor more hydrogen of the alkylene group with a substituent(s) listedunder the definition of “substituted.”

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused fashion. Cycloalkyl groups can contain 3 to 10 atoms in thering(s) or 3 to 8 atoms in the ring(s). Typical cycloalkyl groupsinclude, but are in no way limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl groupmay be unsubstituted or substituted.

As used herein, “cycloalkyl” refers to all carbon ring systems. Suchsystems can be unsaturated, can include some unsaturation, or cancontain some aromatic portion, or be all aromatic. Cycloalkyl group cancontain from 3 to 30 carbon atoms. A cycloalkyl group may beunsubstituted or substituted.

As used herein, “cycloalkylalkyl” refers to an -(alkylene)-R radicalwhere R is cycloalkyl as defined above. Examples include, but are notlimited to, cyclopropylmethyl and cyclohexylmethyl. A cycloalkylalkylgroup may also be referred to as, for example, a (C₁-C₆alkyl)-cycloalkyl group. A cycloalkylalkyl group may be unsubstituted orsubstituted.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic aromatic ring system (including, e.g., fused, bridged, orspiro ring systems where two carbocyclic rings share a chemical bond,e.g., one or more aryl rings with one or more aryl or non-aryl rings)that has a fully delocalized pi-electron system throughout at least oneof the rings. The number of carbon atoms in an aryl group can vary. Forexample, the aryl group can be a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group,or a C₆ aryl group. Examples of aryl groups include, but are not limitedto, benzene, naphthalene, and azulene. An aryl group may be substitutedor unsubstituted.

As used herein, “aralkyl” refers to an -(alkylene)-R radical where R isaryl as defined above. Examples include, but are not limited to, benzyland phenethyl. An aralkyl group may also be referred to as, for example,a (C₁-C₆ alkyl)-aryl group. An aralkyl group may be substituted orunsubstituted.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system (a ring system having a least one ring with a fullydelocalized pi-electron system) that contain(s) one or more heteroatoms,that is, an element other than carbon, including but not limited to,nitrogen, oxygen, and sulfur, and at least one aromatic ring. The numberof atoms in the ring(s) of a heteroaryl group can vary. For example, theheteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atomsin the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term“heteroaryl” includes fused ring systems where two rings, such as atleast one aryl ring and at least one heteroaryl ring, or at least twoheteroaryl rings, share at least one chemical bond. Examples ofheteroaryl rings include, but are not limited to, furan, furazan,thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole,indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole,isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline,isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Aheteroaryl group may be substituted or unsubstituted.

As used herein, “heteroaralkyl” refers to an -(alkylene)-R radical whereR is heteroaryl as defined above. Examples include, but are not limitedto, methylpyridyl and methylpyrimidyl. A heteroaralkyl group may also bereferred to as, for example, a (C₁-C₆ alkyl)-heteroaryl group. Aheteroaralkyl group may be substituted or unsubstituted.

As used herein, “heterocyclic” or “heterocyclyl” refers to three-,four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-memberedmonocyclic, bicyclic, and tricyclic ring system wherein carbon atomstogether with from 1 to 5 heteroatoms constitute said ring system. Aheterocycle may optionally contain one or more unsaturated bondssituated in such a way, however, that a fully delocalized pi-electronsystem does not occur throughout all the rings. The heteroatoms areindependently selected from oxygen, sulfur, and nitrogen. A heterocyclemay further contain one or more carbonyl or thiocarbonylfunctionalities, so as to make the definition include oxo-systems andthio-systems such as lactams, lactones, cyclic imides, cyclicthioimides, and cyclic carbamates. When composed of two or more rings,the rings may be joined together in a fused fashion. Additionally, anynitrogens in a heterocycle may be quaternized. Examples of such“heterocyclic” groups include but are not limited to, 1,3-dioxin,1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane,1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole,1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine,maleimide, succinimide, barbituric acid, thiobarbituric acid,dioxopiperazine, hydantoin, dihydrouracil, trioxane,hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline,isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline,thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine,piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone,pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran,tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide,thiamorpholine sulfone, and their benzo-fused analogs (e.g.,benzimidazolidinone, tetrahydroquinoline, 3,4-methylenedioxyphenyl).Heterocyclyl groups may be substituted or unsubstituted.

As used herein, “heterocyclylalkyl” refers to an -(alkylene)-R radicalwhere R is heterocyclyl as defined above. Examples include, but are notlimited to, methylpyrrolidinyl and methylpiperidinyl. Aheterocyclylalkyl group may also be referred to as, for example, a(C₁-C₆ alkyl)-heterocyclyl group. A heterocyclylalkyl group may besubstituted or unsubstituted.

As used herein, “alkoxy” refers to the formula —OR wherein R is an alkylas defined above. A non-limiting list of alkoxys is methoxy, ethoxy,n-propoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. An alkoxymay be substituted or unsubstituted.

As used herein, “alkoxyalkyl” refers to an alkyl as defined above whichis substituted with one or two alkoxy groups as defined above. Examplesinclude, but are not limited to methoxyethyl, ethoxyethyl, andmethoxypropyl. An alkoxyalkyl group may be substituted or unsubstituted.

As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, oraryl, as defined above, connected as substituents via a carbonyl group,as defined herein. Examples include formyl, acetyl, benzoyl, and acryl,with preferred acyl groups being C₁-C₆ alkyl carbonyl groups. An acylmay be substituted or unsubstituted.

As used herein, “hydroxyalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a hydroxy group. Exemplaryhydroxyalkyl groups include but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. A hydroxyalkylmay be substituted or unsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Such groups includebut are not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. Ahaloalkyl may be substituted or unsubstituted.

As used herein, “haloalkoxy” refers to an alkoxy group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups includebut are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy and 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy. Ahaloalkoxy may be substituted or unsubstituted.

As used herein, “aryloxy” refers to —OR, in which R is an aryl, asdefined above, such as but not limited to phenyl. An aryloxy may besubstituted or unsubstituted.

The term “ester” refers to a “—C(═O)OR” group in which R can be, forexample, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, orcycloalkyl. An ester may be substituted or unsubstituted.

The term “unsubstituted amino” as used herein refers to a —NH₂ group.

The term “substituted amino” as used herein refers to a —NR_(a)R_(b)group, wherein R_(a) and R_(b) are independently selected from hydrogen,alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, aralkyl,heteroaralkyl, cycloalkylalkyl, and heterocyclylalkyl, as definedherein; and not more than one of wherein R_(a) and R_(b) can behydrogen.

As used herein, the term “hydroxy” refers to a —OH group.

A “cyano” group refers to a “—CN” group.

A “carbonyl” group refers to a C═O group.

The term “halogen atom” or “halogen” as used herein, means any one ofthe radio-stable atoms of column 7 of the Periodic Table of theElements, such as, fluorine, chlorine, bromine, and iodine.

In all of the definitions described herein, the terms used to define anew term are as previously defined herein.

Where the numbers of substituents is not specified (e.g., haloalkyl),there may be one or more substituents present. For example “haloalkyl”may include one or more of the same or different halogens. As anotherexample, “C₁-C₃ alkoxyphenyl” may include one or more of the same ordifferent alkoxy groups containing one, two, or three atoms.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

The terms “protecting group” and “protecting groups” as used hereinrefer to any atom or group of atoms that is added to a molecule in orderto prevent existing groups in the molecule from undergoing unwantedchemical reactions. Examples of protecting group moieties are describedin T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W. McOmie,Protective Groups in Organic Chemistry Plenum Press, 1973, both of whichare hereby incorporated by reference for the limited purpose ofdisclosing suitable protecting groups. The protecting group moiety maybe chosen in such a way, that they are stable to certain reactionconditions and readily removed at a convenient stage using methodologyknown from the art. A non-limiting list of protecting groups includebenzyl; substituted benzyl; alkylcarbonyls (e.g., t-butoxycarbonyl(BOC), acetyl, or isobutyryl); arylalkylcarbonyls (e.g.,benzyloxycarbonyl or benzoyl); substituted methyl ether (e.g.,methoxymethyl ether); substituted ethyl ether; a substituted benzylether; tetrahydropyranyl ether; silyl ethers (e.g., trimethylsilyl,triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, ort-butyldiphenylsilyl); esters (e.g., benzoate ester); carbonates (e.g.,methoxymethylcarbonate); sulfonates (e.g., tosylate or mesylate);acyclic ketal (e.g., dimethyl acetal); cyclic ketals (e.g., 1,3-dioxaneor 1,3-dioxolanes); acyclic acetal; cyclic acetal; acyclic hemiacetal;cyclic hemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or1,3-dithiolane); and triarylmethyl groups (e.g., trityl;monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr); or4,4′,4″-trimethoxytrityl (TMTr)).

“Leaving group” as used herein refers to any atom or moiety that iscapable of being displaced by another atom or moiety in a chemicalreaction. More specifically, in some embodiments, “leaving group” refersto the atom or moiety that is displaced in a nucleophilic substitutionreaction. In some embodiments, “leaving groups” are any atoms ormoieties that are conjugate bases of strong acids. Examples of suitableleaving groups include, but are not limited to, tosylates and halogens.Non-limiting characteristics and examples of leaving groups can befound, for example in Organic Chemistry, 2d ed., Francis Carey (1992),pages 328-331; Introduction to Organic Chemistry, 2d ed., AndrewStreitwieser and Clayton Heathcock (1981), pages 169-171; and OrganicChemistry, 5^(th) ed., John McMurry (2000), pages 398 and 408; all ofwhich are incorporated herein by reference for the limited purpose ofdisclosing characteristics and examples of leaving groups.

The term “pharmaceutically acceptable salt” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,HCl or HBr), H₂SO₄, HNO₃, and H₃PO₄. Pharmaceutical salts can also beobtained by reacting a compound with an organic acid such as aliphaticor aromatic carboxylic or sulfonic acids, for example formic acid, AcOH,propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid,fumaric acid, trifluoroacetic acid, benzoic acid, cinnamic acid,mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid,citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearicacid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid,valproic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid, or naphthalenesulfonicacid. Pharmaceutical salts can also be obtained by reacting a compoundwith a base to form a salt such as an ammonium salt, an alkali metalsalt, such as a Li, Na, or a K salt, an alkaline earth metal salt, suchas a Ca, Mg, or Al salt, a salt of organic bases such asdicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,a C₁-C₇ alkylamine, cyclohexylamine, dicyclohexylamine, triethanolamine,ethylenediamine, ethanolamine, diethanolamine, triethanolamine,tromethamine, and salts with amino acids such as arginine and lysine; ora salt of an inorganic base, such as Al(OH)₃, Ca(OH)₂, KOH, Na₂CO₃,NaOH, or the like.

Some embodiments provide pharmaceutically acceptable salts of Formula(II). In some embodiments, the salt is selected from the groupconsisting of hydrochloride, sulfate, hemisulfate, acetate, fumarate,malate, and citrate.

The term “solvate” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to mean that the solvent is complexed with acompound in a reproducible molar ratio, including, but not limited to,0.5:1, 1:1, or 2:1. Thus, the term “pharmaceutically acceptablesolvate,” refers to a solvate wherein the solvent is one that does notcause significant irritation to an organism to which it is administeredand does not abrogate the biological activity of the compound.

Some embodiments provide solvates of Formula (I). In some embodiments,the solvent in the solvate is selected from water, ethanol, and acetone,or combinations thereof.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, or maybe stereoisomeric mixtures, and include all diastereomeric, andenantiomeric forms. In addition it is understood that, in any compounddescribed herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof. Stereoisomers are obtained,if desired, by methods such as, stereoselective synthesis and/or theseparation of stereoisomers by chiral chromatographic columns. Likewise,it is understood that, in any compound described, all tautomeric formsare also intended to be included.

Wherever a substituent is depicted as a di-radical (i.e., has two pointsof attachment to the rest of the molecule), it is to be understood thatthe substituent can be attached in any directional configuration unlessotherwise indicated. Thus, for example, a substituent depicted as -AE-or

includes the substituent being oriented such that the A is attached atthe leftmost attachment point of the molecule as well as the case inwhich A is attached at the rightmost attachment point of the molecule.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensand/or deuteriums.

It is understood that the compounds described herein can be labeledisotopically or by another other means, including, but not limited to,the use of chromophores or fluorescent moieties, bioluminescent labels,or chemiluminescent labels. Substitution with isotopes such as deuteriummay afford certain therapeutic advantages resulting from greatermetabolic stability, such as, for example, increased in vivo half-lifeor reduced dosage requirements. Each chemical element as represented ina compound structure may include any isotope of said element. Forexample, in a compound structure a hydrogen atom may be explicitlydisclosed or understood to be present in the compound. At any positionof the compound that a hydrogen atom may be present, the hydrogen atomcan be any isotope of hydrogen, including but not limited to hydrogen-1(protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus,reference herein to a compound encompasses all potential isotopic formsunless the context clearly dictates otherwise.

It is understood that the methods and formulations described hereininclude the use of salts, solvates, hydrates, and conformers ofcompounds of preferred embodiments, as well as metabolites and activemetabolites of these compounds having the same type of activity. Aconformer is a structure that is a conformational isomer. Conformationalisomerism is the phenomenon of molecules with the same structuralformula but different conformations (conformers) of atoms about arotating bond. In specific embodiments, the compounds described hereinexist in solvated forms with pharmaceutically acceptable solvents suchas water, ethanol, or the like. In other embodiments, the compoundsdescribed herein exist in unsolvated form. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, or the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. In addition, the compounds provided herein can existin unsolvated as well as solvated forms. In general, the solvated formsare considered equivalent to the unsolvated forms for the purposes ofthe compounds and methods provided herein. Compounds of Formula (I) canalso be provided as, for example, amorphous forms, milled forms andnano-particulate forms.

Likewise, it is understood that the compounds described herein, such ascompounds of preferred embodiments, include the compound in any of theforms described herein (e.g., pharmaceutically acceptable salts,crystalline forms, amorphous form, solvated forms, enantiomeric forms,tautomeric forms, and the like).

Dosing Regimes

In some embodiments, about 1 mg to about 5 grams of a compound ofFormula (I) is administered each day. In some embodiments, about 2 mg toabout 2 grams of a compound of Formula (I) is administered each day. Insome embodiments, the amount of a compound of Formula (I) administeredeach day is, or is about, 5 mg to 1 gram; 10 mg to 800 mg; 20 mg to 600mg; 30 mg to 400 mg; 40 mg to 200 mg; 50 mg to 100 mg; or any amount inbetween.

In some embodiments, about 1 mg to about 5 grams of a compound ofFormula (I) is administered each week. In some embodiments, about 2 mgto about 2 grams of a compound of Formula (I) is administered each week.In some embodiments, the amount of a compound of Formula (I)administered each week is, or is about, 5 mg to 1 gram; 10 mg to 800 mg;20 mg to 600 mg; 30 mg to 400 mg; 40 mg to 200 mg; 50 mg to 100 mg; orany amount in between.

In some embodiments, about 1 mg to about 5 grams of a compound ofFormula (I) is administered each cycle of treatment. In someembodiments, about 2 mg to about 2 grams of a compound of Formula (I) isadministered each cycle of treatment. In some embodiments, the amount ofa compound of Formula (I) administered each cycle of treatment is, or isabout, 5 mg to 1 gram; 10 mg to 800 mg; 20 mg to 600 mg; 30 mg to 400mg; 40 mg to 200 mg; 50 mg to 100 mg; or any amount in between.

In some embodiments, a compound of Formula (I) is administered at leastonce per day; twice per day; three times per day; or four times per day.In some embodiments, a compound of Formula (I) is administered at leastonce per week; twice per week; three times per week; or four times perweek. In some embodiments, each cycle of treatment lasts 1 day; 2 days;3 days; 4 days; 5 days; 6 days; 7 days; 8 days; 9 days; 10 days; 11days; 12 days; 13 days; 14 days, or any time in between. In someembodiments, each cycle of treatment has at least 1 day; 2 days; 3 days;4 days; 5 days; 6 days; 7 days; 8 days; 9 days; 10 days; 11 days; 12days; 13 days; or 14 days, between administrations of a compound ofFormula (I).

In some embodiments, a compound of Formula (I) is provided intravenouslyover about 10 min; about 20 min; about 30 min; about 1 hour; about 1.5hrs; about 2 hrs; about 2.5 hrs; about 3 hrs; about 3.5 hrs; about 4hrs, or any time in between.

EXAMPLES

Additional embodiments are disclosed in further detail in the followingexamples, which are not in any way intended to limit the scope of theclaims.

Characterization of the compounds disclosed herein was performed withBruker AV-500 and DRX-500 NMR spectrometers and a Perkin Elmer PE-SCIEXAPI-150 mass spectrometer.

In the synthetic procedures described herein, “workup and purification”refers to combining organic layers after an aqueous phase extraction,washing with brine, drying over Na₂SO₄, filtering, concentrating, andpurified by silica gel chromatography with the indicated solvent system.The workup and purification may also include an optional washing stepwith 10% aq. Na₂S₂O₃/sat. aq. NaHCO₃ (1:1) prior to the wash with brine.

Example 1 Compound 1:(S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)azepane-2,7-dione

To a solution of 4-(diethoxymethyl)benzaldehyde (2.43 g, 11.67 mmol) inMeOH (40 mL) at 0° C. was added NaBH₄ (886.7 mg, 23.34 mmol). Thesuspension was stirred at RT for 3 h. The solvent was then removed, andthe residue was diluted with water and extracted with DCM. The combinedorganic layers were dried over Na₂SO₄, filtered, concentrated, and theresidue purified by silica gel chromatography with EtOAc in pet. ether(10% to 23%) to give (4-(diethoxymethyl)phenyl)methanol 1.1 (2.21 g, 90%yield) as a colorless oil. MS (ESI) m/z 165.1 [M−42]⁺.

To a solution of compound 1.2 (323 mg, 1.24 mmol) in THF (20 mL) at 0°C. was added 1.1 (326.5 mg, 1.55 mmol) followed by PPh₃ (650.4 mg, 2.48mmol). A solution of DEAD (431.9 mg, 2.48 mmol) in THF (1 mL) was addeddropwise and the suspension was stirred at RT for 16 h. The solvent wasremoved, and the residue was purified by silica gel chromatography usingEtOAc in pet. ether (40% to 100%) to give compound 1.3 (373 mg, 66.7%yield) as a white solid. MS (ESI) m/z 407.1 [M−45]⁺.

To a solution of compound 1.3 (473 mg, 1.05 mmol) in THF (10 mL) at RTwas added 4 M HCl (1.31 mL), and the reaction was stirred at RT for 30min. The solvent was removed, and the residue was dried under vacuum togive compound 1.4 (397 mg, 100% yield) as a white solid. MS (ESI) m/z379.1 [M+1]⁺.

To a solution of compound 1.4 (396.9 mg, 1.05 mmol) influorobenzene/DMSO (30 mL/5 mL, 1 drop water in DMSO) was addedDess-Martin reagent (1.12 g, 2.63 mmol). The suspension was heated at80° C. for 18 h. Additional Dess-Martin reagent (550 mg) was added andthe mixture was heated at 80° C. for 5 h. The mixture was cooled to RTand filtered. The filtrate was added to sat. aq. Na₂S₂O₃. The suspensionwas stirred at 0° C. for 5 min then extracted with DCM. Workup andpurification by silica gel chromatography using EtOAc in pet. ether(40-100%) provided compound 1.5 (184 mg, 45% yield) as a white solid. MS(ESI) m/z 393.1 [M+1]⁺.

To a solution of compound 1.5 (76 mg, 0.194 mmol) in DCM (10 mL) wasadded morpholine (25.3 mg, 0.291 mmol) followed by NaBH(OAc)₃ (82.3 mg,0.384 mmol). The mixture was stirred at RT for 48 h, concentrated,purified by prep-TLC using EtOAc then further purified by prep-HPLC (5μM C18 column, 0.1% TFA in H₂O, 0.1% TFA in ACN, 5%-95% 0.1% TFA in ACN)to afford Compound 1 (30.7 mg, 21.7% yield) as a white solid. ¹H NMR(DMSO-d₆, 400 MHz) δ: 10.70 (s, 1H), 7.49-7.45 (m, 3H), 7.35-7.31 (m,4H), 5.24-5.21 (m, 3H), 4.47 (s, 2H), 3.57 (s, 4H), 3.47 (s, 2H), 3.08(t, J=11.2 Hz, 1H), 2.59-2.54 (m, 1H), 2.35 (s, 5H), 2.12-1.97 (m, 2H),1.86-1.74 (m, 1H). MS (ESI) m/z 464.1 [M+H]⁺.

Example 2 Compound 2:(S)-3-(4-((4-((2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)azepane-2,7-dione

To a solution of compound 1.5 (90 mg, 0.229 mmol) in AcOH (4 mL) at RTwas added 3,4-dihydro-2H-benzo[b][1,4]oxazine (46.5 mg, 0.344 mmol)followed by NaBH(OAc)₃ (145.6 mg, 0.687 mmol). The mixture was stirredat RT for 3 h, the solvent removed, and the residue purified by prep-TLCusing EtOAc in pet. ether (1:2) then further purified by prep-HPLC aspreviously described to afford Compound 2 (45.0 mg, 39% yield) as awhite solid. ¹H NMR (DMSO-d₆, 400 MHz) δ: 10.69 (s, 1H), 7.49-7.45 (m,3H), 7.35-7.31 (m, 4H), 6.70-6.63 (m, 3H), 6.51 (t, J=7.2 Hz, 1H),5.23-5.19 (m, 3H), 4.47 (d, J=8.8 Hz, 4H), 4.21 (t, J=3.6 Hz, 2H),3.39-3.35 (m, 2H), 3.06 (t, J=13.2 Hz, 1H), 2.57 (d, J=18.0 Hz, 1H),2.36-2.29 (m, 1H), 2.09-1.99 (m, 2H), 1.85-1.74 (m, 1H). MS (ESI) m/z512.2 [M+H]⁺.

Example 3 Compound 3:((S)-3-(4-((3-chloro-4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)azepane-2,7-dione

To a solution of methyl 3-chloro-4-formylbenzoate (500 mg, 2.52 mmol) inmethanol (10 mL) at RT was added 2,2-dimethoxypropane (393.6 mg, 3.78mmol) followed by p-TsOH (48 mg, 0.252 mmol). The mixture was refluxedfor 16 h, the solvent was removed, the residue diluted with EtOAc (10mL), washed with sat. aq. NaHCO₃, dried over Na₂SO₄, filtered, andconcentrated to give methyl 3-chloro-4-(dimethoxymethyl) benzoate (540mg, 87.8% yield) as a yellow oil. ¹H NMR (DMSO-d₆, 300 MHz) δ 7.94 (s,2H), 7.71 (d, J=8.4 Hz, 1H), 5.60 (s, 1H), 3.87 (s, 3H), 3.31 (d, J=0.9Hz, 6H).

To a solution of methyl 3-chloro-4-(dimethoxymethyl)benzoate (480 mg,2.05 mmol) in THF (20 mL) at 0° C. was added LiAlH₄ (3.074 mL, 1 M inTHF). The suspension was stirred at RT for 2 h. To the reaction wasslowly added water (1 mL) then 10% NaOH (2 mL) followed by water (1 mL).The suspension was filtered, and the filtrate was extracted with EtOAc.The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to give crude (3-chloro-4-(dimethoxymethyl)phenyl) methanol3.1 (380 mg) as a yellow oil, which was used directly in the next stepwithout further purification. ¹H NMR (CDCl₃, 300 MHz) δ 7.60 (d, J=8.1Hz, 1H), 7.39 (s, 1H), 7.26 (d, J=7.2 Hz, 1H), 5.63 (s, 1H), 4.67 (s,2H), 3.38 (d, J=0.9 Hz, 6H).

To a solution of compound 3.1 (264 mg, 1.22 mmol) in THF (15 mL) at 0°C. was added compound 3.2 (260 mg, 1.0 mmol) followed by PPh₃ (524.6 mg,2.0 mmol). A solution of DEAD (348.3 mg, 2.0 mmol) in THF (1 mL) wasadded dropwise and the suspension was stirred at RT for 16 h. Thesolvent was removed, and the residue was purified by silica gelchromatography with EtOAc in pet. ether (40% to 100%) to give compound3.3 (262 mg, 39% yield) as a white solid. MS (ESI) m/z 427.1 [M−31]⁺.

To a solution of compound 3.3 (262 mg, 0.572 mmol) in THF (10 mL) at RTwas added 4 M HCl (0.72 mL). The reaction was stirred at RT for 1 hour.The solvent was removed, and the residue was dried under vacuum to givecompound 3.4 (235.7 mg, 100% yield) as a white solid. MS (ESI) m/z 413.0[M+1]⁺.

To a solution of compound 3.4 (235.7 mg, 0.572 mmol) influorobenzene/DMSO (30 mL/5 mL, 1 drop water in DMSO) was addedDess-Martin reagent (607 mg, 1.43 mmol). The suspension was heated at80° C. for 18 h then cooled to RT. Additional Dess-Martin reagent (303mg) was added and the mixture was heated at 80° C. for 5 h and cooled toRT. The suspension was filtered, and the filtrate was added to sat. aq.Na₂S₂O₃ (30 mL). The suspension was stirred at 0° C. for 5 min thenextracted with DCM. Workup and purification by silica gel chromatographyusing EtOAc in pet. ether (20% to 80%) provided compound 3.5 (72 mg, 30%yield) as a white solid. MS (ESI) m/z 427.0 [M+1]⁺.

To a solution of compound 3.5 (54 mg, 0.127 mmol) in DCM (5 mL) at RTwas added morpholine (22.1 mg, 0.254 mmol) followed by NaBH(OAc)₃ (80.8mg, 0.38 mmol). The mixture was stirred at RT for 24 h. The solvent wasremoved, and the residue was purified by prep-TLC using EtOAc/petroleumether (2:1) then by prep-HPLC, as previously described, to affordCompound 3 (19.9 mg, 32% yield) as a white solid. ¹H NMR (DMSO-d₆, 400MHz) δ: 10.70 (s, 1H), 7.57 (s, 1H), 7.53-7.45 (m, 3H), 7.33 (t, J=6.8Hz, 2H), 5.27 (s, 2H), 5.20 (d, J=5.2 Hz, 1H), 4.49 (s, 2H), 3.59-3.56(m, 6H), 3.11-3.03 (m, 1H), 2.58 (d, J=17.2 Hz, 1H), 2.42 (s, 4H),2.38-2.33 (m, 1H), 2.14-1.99 (m, 2H), 1.86-1.76 (m, 1H). MS (ESI) m/z498.1 [M+H]⁺.

Example 4 Compound 4:(S)-3-(4-{[p-(4-Piperidyl)phenyl]methoxy}-2-isoindolinoyl)-2,7-azepanedione

To a solution of ethyl 4-iodobenzoate (750 mg, 2.72 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(923 mg, 2.99 mmol) in DMF (50 mL) at RT were added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (400 mg) andK₂CO₃ (1.12 g, 8.16 mmol). The suspension was stirred at 85° C. for 16hrs. The mixture was filtered through a pad of Celite. The filtrate wasdiluted with water and extracted with EtOAc. Workup and purificationwith petroleum ether/EtOAc (8:1) provided 4-tert-butyl 4′-ethyl1,2,3,6-tetrahydro-[1,1′-biphenyl]-4,4′-dicarboxylate (720 mg, 80%yield) as a white solid.

To a solution of 4-tert-butyl 4′-ethyl1,2,3,6-tetrahydro-[1,1′-biphenyl]-4,4′-dicarboxylate (720 mg, 2.18mmol) in EtOH (20 mL) was added palladium on activated carbon (80 mg) atRT. The mixture was stirred at RT for 3 hrs. The mixture was filteredthrough a pad of Celite and the filtrate was concentrated to obtain thecrude product, which was purified by silica gel chromatography elutingwith petroleum ether/EtOAc (7:1) to give ethyl4-(4-(tert-butoxycarbonyl)cyclohexyl)benzoate (680 mg, 93% yield) as acolorless oil.

To a solution of ethyl 4-(4-(tert-butoxycarbonyl)cyclohexyl)benzoate(680 mg, 2.04 mmol) in THF (15 mL) at 0° C. was added LAH (1.0 M in THF,1.63 mL, 4.08 mmol) dropwise. The mixture was stirred at RT for 2 hrs.The reaction was quenched with Na₂SO₄ decahydrate (5.0 g). Afterstirring at RT for 1 hour, the mixture was filtered, concentrated, andpurified by silica gel chromatography eluting with MeOH in DCM (3%) togive tert-butyl 4-(4-(hydroxymethyl)phenyl)piperidine-1-carboxylate (410mg, 69% yield) as a white solid.

To a solution of tert-butyl4-(4-(hydroxymethyl)phenyl)piperidine-1-carboxylate (186 mg, 0.64 mmol),(S)-4-hydroxy-2-(2-oxoazepan-3-yl)isoindolin-1-one (200 mg, 0.51 mmol),triphenylphosphine (524 mg, 1.024 mmol) in THF (10 mL) at 0° C. wasadded DEAD (178 mg, 1.024 mmol) dropwise. The mixture was stirred at RTfor 16 hrs then concentrated to give the crude product which waspurified by prep-HPLC (5 μM C18 column, 0.1% TFA in H₂O, 0.1% TFA inACN, 5%-95% 0.1% TFA in ACN) to afford (5)-tert-butyl4-(4-(((1-oxo-2-(2-oxoazepan-3-yl)isoindolin-4-yl)oxy)methyl)phenyl)piperidine-1-carboxylate (200 mg, 56% yield) as awhite solid. MS (ESI) m/z 478.1 [M+H-^(t)Bu]⁺.

To a solution of (S)-tert-butyl4-(4-(((1-oxo-2-(2-oxoazepan-3-yl)isoindolin-4-yl)oxy)methyl)phenyl)piperidine-1-carboxylate (200 mg, 0.375 mmol) influorobenzene/DMSO (10 mL/1 mL, 1 drops water in DMSO) at RT was addedDess-Martin reagent (397 mg, 0.94 mmol). The mixture was heated to 80°C. for 18 hrs. The mixture was then cooled to 0° C. and quenched withsat. aqueous sodium thiosulfate solution (25 mL). After stirring at 0°C. for 15 min, the mixture was extracted with DCM. Workup andpurification with EtOAc/pet. ether (20% to 80%) provided (S)-tert-butyl4-(4-(((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)phenyl)piperidine-1-carboxylate (32 mg, 15% yield) as a white solid.

To a solution of (S)-tert-butyl4-(4-(((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)phenyl)piperidine-1-carboxylate (110 mg, 0.2 mmol) in DCM (4mL) was added TFA (1 mL). The mixture was stirred at RT for 2 hrs then asat. NaHCO₃ solution was added to reach pH=7, and the mixture wasextracted with DCM. The combined organic phases were dried overanhydrous Na₂SO₄, filtered, and concentrated to give the crude productwhich was purified by prep-HPLC as previously described to affordCompound 4 (2.5 mg, 6.2% yield) as a white solid. ¹H NMR (DMSO-d₆, 400MHz) δ: 10.71 (s, 1H), 8.64 (s, 1H), 8.40 (s, 1H), 7.49 (m, 3H), 7.31(m, 4H), 5.23 (m, 3H), 3.12 (s, 2H), 2.85 (m, 2H), 2.55 (m, 3H), 2.32(m, 1H), 2.12 (m, 4H), 2.07 (m, 3H). MS (ESI) m/z 448.0 [M+H]⁺.

Example 5 Compound 5:(S)-3-(4-{[p-(Aminomethyl)phenyl]methoxy}-2-isoindolinoyl)-2,7-azepanedionetrifluoroacetic Acid

To a solution of tert-butyl(3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)carbamate(120 mg, 0.205 mmol) in DCM (8 mL) at RT was added TFA (2 mL). Themixture was stirred for 2 hrs. The solvent was evaporated to give3-((2-((4-(3-aminopropoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)-N-(tert-butyl)benzenesulfonamide(102 mg, crude) which was used directly in the next step without furtherpurification. MS (ESI) m/z 485.1 [M+H]⁺.

To a solution of (S)-4-hydroxy-2-(2-oxoazepan-3-yl)isoindolin-1-one (700mg, 2.69 mmol), tert-butyl 4-(hydroxymethyl)benzylcarbamate (804 mg,3.37 mmol), and triphenylphosphine (1.41 g, 5.38 mmol) in THF (10 mL) atRT was added a solution of DEAD (938.7 mg, 5.38 mmol) in THF (1 mL). Themixture was stirred at RT for 16 hrs. The solvent was evaporated, andthe residue was purified by silica gel chromatography eluting with MeOHin DCM (from 0% to 7%) to give (S)-tert-butyl4-(((1-oxo-2-(2-oxoazepan-3-yl)isoindolin-4-yl)oxy)methyl)benzylcarbamate (674 mg, 52% yield) as a white solid. MS (ESI) m/z 480.2[M+H]⁺.

To a solution of (S)-tert-butyl4-(((1-oxo-2-(2-oxoazepan-3-yl)isoindolin-4-yl)oxy)methyl)benzylcarbamate (674 mg, 1.41 mmol) in fluorobenzene/DMSO (30mL/5 mL, 1 drops H₂O in DMSO) at RT was added Dess-Martin reagent (1.49g, 3.52 mmol). The mixture was stirred at 80° C. for 16 hrs. The mixturewas cooled to RT and filtered. The filtrate was added to a cooled sat.aqueous sodium thiosulfate solution (30 mL) and stirred at 0° C. for 5min then extracted with DCM. Workup and purification withEtOAc/petroleum ether from 40% to 100% provided (S)-tert-butyl4-(((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate (320 mg, 46% yield) as a white solid. MS(ESI) m/z 494.2[M+H]⁺.

To a solution of (S)-tert-butyl4-(((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate (22 mg, 0.0446 mmol) in DCM (2 mL) was addedTFA (0.5 mL) at RT. The mixture was stirred at RT for 2 hrs. The solventwas evaporated to give the desired product which was lyophilized toafford Compound 5 (17.6 mg, 78% yield) as a white solid. MS (ESI) m/z394.1 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.71 (s, 1H), 8.18 (s, 1H),7.55 (d, J=7.6 Hz, 2H), 7.48-7.45 (m, 3H), 7.33-7.30 (m, 2H), 5.30 (s,2H), 5.23 (dd, J=4.8, 12.4 Hz, 1H), 4.48 (s, 2H), 4.05 (d, J=5.2 Hz,2H), 3.11-3.05 (m, 1H), 2.60-2.53 (m, 1H), 2.34-2.31 (m, 1H), 2.11-1.99(m, 2H), 1.85-1.80 (m, 1H).

Example 6 Compound 6:(S)-3-(4-{[p-({2-[3-(p-{5-Methyl-4-[m-(tert-butylaminosulfonyl)phenylamino]-2-pyrimidinylamino}phenoxy)propylamino]acetylamino}methyl)phenyl]methoxy}-2-isoindolinoyl)-2,7-azepanedione

To a solution of(S)-3-(4-((4-(aminomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)azepane-2,7-dione(112 mg, 0.284 mmol) in DCM (5 mL) at RT was added TEA (24.2 mg, 0.175mmol) followed by 2-bromoacetyl chloride (45 mg, 0.284 mmol). Themixture was stirred for 1 hour. The solvent was evaporated, and theresidue was purified by silica gel chromatography eluting withEtOAc/petroleum ether from 20% to 100% to give(S)-2-bromo-N-(4-(((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)acetamide(89 mg, 61% yield) as a white solid. MS (ESI) m/z 514.1 [M+H]⁺.

To a solution of(S)-2-bromo-N-(4-(((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)acetamide (45 mg, 0.0877 mmol) in DMF (5 mL) at RT wasadded K₂CO₃ (24.2 mg, 0.175 mmol) followed by3-((2-((4-(3-aminopropoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)-N-(tert-butyl)benzenesulfonamide(45 mg, 0.0877 mmol). The mixture was heated at 50° C. for 2 hrs. Thesolvent was evaporated, and the residue was purified by prep-HPLC aspreviously described to afford Compound 6 (12.6 mg, 16% yield) as awhite solid. MS (ESI) m/z 917.7 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ10.71 (s, 1H), 8.77 (s, 1H), 8.53 (s, 1H), 8.12 (d, J=8.0 Hz, 2H), 7.89(s, 1H), 7.55-7.41 (m, 9H), 7.31-7.27 (m, 4H), 6.77 (d, J=8.8 Hz, 2H),5.23-5.18 (m, 3H), 4.44 (s, 2H), 4.31 (d, J=5.6 Hz, 2H), 3.96 (t, J=6.4Hz, 2H), 3.09-3.01 (m, 2H), 2.74-2.67 (m, 2H), 2.58-2.53 (m, 2H),2.32-2.26 (m, 1H), 2.11 (s, 3H), 2.04-1.97 (m, 3H), 1.87-1.84 (m, 3H),1.12 (s, 9H).

Example 7 Compound 7:(S)-3-(6-Fluoro-4-{[p-(morpholinomethyl)phenyl]methoxy}-2-isoindolinoyl)-2,7-azepanedione

To a cooled (−15° C.) solution of 5-fluoro-2-methylbenzoic acid (1.0 g,6.5 mmol) in sulfuric acid (8 mL) at RT was added nitric acid (0.44 mL)dropwise. The mixture was stirred for 1 hour then warmed to 0° C.stirred for 1 hour. The mixture was poured slowly into ice water andextracted with EtOAc. The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give5-fluoro-2-methyl-3-nitrobenzoic acid (830 mg, crude) which was used inthe next step without further purification.

To a solution of 5-fluoro-2-methyl-3-nitrobenzoic acid (830 mg crude) inMeOH (8 mL) at 0° C. was added thionyl chloride (1 mL) dropwise. Themixture was then heated to reflux for 3 hrs. The solvent was evaporatedto give the crude product which was purified by silica gelchromatography using petroleum ether/EtOAc (100:1 to 50:1) to affordmethyl 5-fluoro-2-methyl-3-nitrobenzoate (530 mg, 59% yield) as a yellowsolid.

To a solution of methyl 5-fluoro-2-methyl-3-nitrobenzoate (530 mg, 2.66mmol) in MeOH (6 mL) at RT was added Pd/C (400 mg). The suspension wasstirred at RT for 3 hrs under H₂. The suspension was filtered through apad of Celite and the filtrate was concentrated to give methyl3-amino-5-fluoro-2-methylbenzoate (420 mg, crude) which was used in thenext step without further purification.

To methyl 3-amino-5-fluoro-2-methylbenzoate (420 mg, 2.28 mmol) in waterat 0° C. was dropwise added sulfuric acid (5 mL) followed sodium nitrate(165 mg, 2.39 mmol, in 2.5 mL water). After stirring at 0° C. for 2.5hrs, the mixture was dropwise added into sulfuric acid (50% in water) at100° C. for 20 min then the mixture was cooled to RT and extracted withEtOAc. The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated to give methyl5-fluoro-3-hydroxy-2-methylbenzoate which was used in the next stepwithout further purification.

To a solution of methyl 5-fluoro-3-hydroxy-2-methylbenzoate (320 mg,1.74 mmol) in DMF (6 mL) 0° C. was added sodium hydride (60%, 84 mg, 2.1mmol). The mixture was stirred at this temperature for 15 min theniodomethane was added. After stirring at 0° C. for 15 min, the mixturewas warmed to RT and stirred for 1 hour. The reaction was quenched withwater and extracted with tert-butyl methyl ether. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered,and concentrated to afford methyl 5-fluoro-3-methoxy-2-methylbenzoate(327 mg crude) which was used in the next step without furtherpurification.

To a solution of methyl 5-fluoro-3-methoxy-2-methylbenzoate (5.4 g, 30.8mmol) in carbon tetrachloride (40 mL) at RT was added NBS (8.2 g, 46.3mmol) and 2,2′-azobis(2-methylpropionitrile) (2.0 mg, 12.3 mmol). Themixture was refluxed overnight, the solvent was evaporated, and thecrude product was purified by silica gel chromatography (petroleumether/EtOAc, 100:1 to 20:1) to afford methyl2-(bromomethyl)-5-fluoro-3-methoxybenzoate (4.6 g, 59% yield) as a whitesolid.

To a solution of (S)-3-aminoazepan-2-one (56 mg, 0.43 mmol) and TEA (72mg, 0.72 mmol in DMF (2 mL) was added a solution of methyl2-(bromomethyl)-5-fluoro-3-methoxybenzoate (100 mg, 0.36 mmol) in DMF (2mL). The mixture was stirred at 50° C. for 3 hrs, concentrated, andwashed with EtOAc to afford(S)-6-fluoro-4-methoxy-2-(2-oxoazepan-3-yl)isoindolin-1-one (100 mg, 95%yield) as a white solid. MS (ESI) m/z 293.0 [M+H]⁺.

To a solution of(S)-6-fluoro-4-methoxy-2-(2-oxoazepan-3-yl)isoindolin-1-one (100 mg,0.34 mmol) in DCM (6 mL), boron tribromide (515 mg, 2.05 mmol in 2 mLDCM) was added at 0° C. After stirring at this temperature for 15 min,the mixture was warmed to RT and stirred for 3 hrs. The reaction wasquenched by water at 0° C., concentrated, and purified by silica gelchromatography (DCM/MeOH, 100:1 to 20:1) to afford(S)-6-fluoro-4-hydroxy-2-(2-oxoazepan-3-yl)isoindolin-1-one (20 mg, 21%yield) as a white solid. MS (ESI) m/z 279.0 [M+H]⁺.

To a solution of(S)-6-fluoro-4-hydroxy-2-(2-oxoazepan-3-yl)isoindolin-1-one (250 mg,0.90 mmol) and (4-(diethoxymethyl)phenyl)MeOH (284 mg, 1.35 mmol),triphenylphosphine (472 mg, 1.8 mmol) in THF (2.5 mL), was added DEAD(373 mg, 1.80 mmol) at 0° C. The mixture was stirred for 15 min, warmedto RT and stirred for 1 hr, the solvent was evaporated and the crudeproduct was purified by silica gel chromatography (DCM/MeOH, 100:1 to50:1) to afford(S)-4-((4-(diethoxymethyl)benzyl)oxy)-6-fluoro-2-(2-oxoazepan-3-yl)isoindolin-1-one(310 mg, 73% yield) as a white solid.

To a solution of(S)-4-((4-(diethoxymethyl)benzyl)oxy)-6-fluoro-2-(2-oxoazepan-3-yl)isoindolin-1-one (120 mg, 0.303 mmol) in fluorobenzene/DMSO (24 mL/6 mL)was added Dess-Martin periodinane reagent (321.3 mg, 0.758 mmol). Themixture was stirred at 80° C. for 16 hrs. After cooling to RT,Dess-Martin reagent (160 mg) was added. The suspension was heated to 80°C. for another 16 hrs. After cooling to RT, the reaction was quenchedwith sat. aqueous sodium thiosulfate solution (15 mL) and stirred for 5min. The resulting mixture was extracted with DCM. Workup andpurification with EtOAc in petroleum ether from 10% to 69% to give(S)-4-(((2-(2,7-dioxoazepan-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)benzaldehyde(45 mg, 36% yield) as a white solid. MS (ESI) m/z 411.1 [M+H]⁺.

To a solution of(S)-4-(((2-(2,7-dioxoazepan-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)benzaldehyde(30 mg, 0.076 mmol) in DCM (4 mL) at RT was added morpholine (13 mg,0.152 mmol) followed by sodium triacetoxyborohydride (32 mg, 0.152mmol). The mixture was stirred at RT for 16 hrs then the solvent wasevaporated. The residue was purified by prep-TLC (EtOAc) to give thecrude product which was purified by prep-HPLC as previously described toafford Compound 7 (5.5 mg, 15% yield) as a white solid. MS (ESI) m/z481.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H), 7.45 (d, J=7.2Hz, 2H), 7.34 (d, J=7.6 Hz, 2H), 7.30 (d, J=8.1 Hz, 1H), 7.11 (d, J=7.2Hz, 1H), 5.32-5.19 (m, 1H), 5.24 (s, 2H), 4.44 (s, 2H), 3.57 (s, 4H),3.47 (s, 2H), 3.21-3.06 (m, 1H), 2.59-2.57 (m, 1H), 2.34 (s, 5H),2.02-1.96 (m, 2H), 1.82-1.75 (m, 1H).

Example 8 Compound 8:(S)-3-{4-[(p-Morpholinocarbonylphenyl)methoxy]-2-isoindolinoyl}-2,7-azepanedione

To a solution of 4-(hydroxymethyl)benzoic acid (500 mg, 3.28 mmol) inDMF (5 mL) was added morpholine (326 mg, 3.94 mmol), followed by HOBt(678.9 mg, 4.92 mmol), EDAC.HCl (944 mg, 4.92 mmol) and DIEA (846.2 mg,6.56 mmol). The mixture was stirred at RT for 16 hrs. The reaction wasdiluted with water (5 mL) and extracted with DCM. Workup andpurification with EtOAc/petroleum ether from 30% to 90% provided(4-(hydroxymethyl)phenyl)(morpholino)methanone (520 mg, 72% yield) as acolorless oil. MS (ESI) m/z 221.1 [M+H]⁺.

To a solution of (S)-4-hydroxy-2-(2-oxoazepan-3-yl)isoindolin-1-one (100mg, 0.385 mmol), (4-(hydroxymethyl)phenyl)(morpholino)methanone (85 mg,1.55 mmol) and triphenylphosphine (201 mg, 0.77 mmol) in THF (3 mL) at0° C. was added a solution of DEAD (134 mg, 0.77 mmol) in THF (1 mL)dropwise. The mixture was stirred at RT for 16 hrs. The solvent wasevaporated, and the residue was purified by prep-TLC (EtOAc) to give(S)-4-((4-(morpholine-4-carbonyl)benzyl)oxy)-2-(2-oxoazepan-3-yl)isoindolin-1-one(135 mg, 76% yield) as a white solid. MS (ESI) m/z=333.1 [M+1]⁺.

To a solution of(S)-4-((4-(morpholine-4-carbonyl)benzyl)oxy)-2-(2-oxoazepan-3-yl)isoindolin-1-one(135 mg, 0.292 mmol) in fluorobenzene/DMSO (12 mL/2 mL, 1 drop H₂O inDMSO) was added Dess-Martin periodinane (309.6 mg, 0.73 mmol). Thesuspension was stirred at 80° C. overnight, cooled to RT, filtered, andthe filtrate was added to sat. aqueous sodium thiosulfate solution (10mL). After stirring at 0° C. for 5 min, the mixture was extracted withDCM. The combined organic layers were washed with 10% sodiumthiosulfate/sat. NaHCO₃ (1:1), and brine, dried over anhydrous Na₂SO₄,filtered, and concentrated to give the crude product which was purifiedby prep-TLC (EtOAc) to afford Compound 8 (52.5 mg, 38% yield) as a whitesolid. MS (ESI) m/z 333.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (s,1H), 7.57 (d, J=8.0 Hz, 2H), 7.51-7.44 (m, 3H), 7.33 (d, J=8.0 Hz, 2H),5.31 (s, 2H), 5.23 (dd, J=5.2, 12.4 Hz, 1H), 4.49 (s, 2H), 3.60 (s, 6H),3.11-3.03 (m, 1H), 2.60-2.54 (m, 1H), 2.38-2.29 (m, 1H), 2.12-1.98 (m,2H), 1.86-1.76 (m, 1H).

Example 9 Compound 9:(S)-3-(4-{[m-(Aminomethyl)phenyl]methoxy}-2-isoindolinoyl)-2,7-azepanedionetrifluoroacetic Acid

To a solution of (S)-4-hydroxy-2-(2-oxoazepan-3-yl)isoindolin-1-one (150mg, 0.577 mmol), 3-(hydroxymethyl)benzonitrile (154 mg, 1.15 mmol) andtriphenylphosphine (378 mg, 1.44 mmol) in THF (3.5 mL) at RT was addedDEAD (251 mg, 1.44 mmol). The mixture was stirred for 30 min. Thesolvent was evaporated, and the residue was purified by prep-TLC(DCM/MeOH, 100:1 to 30:1) to give(S)-3-(((1-oxo-2-(2-oxoazepan-3-yl)isoindolin-4-yl)oxy)methyl)benzonitrile(235 mg, 81% yield) as a white solid. MS (ESI) m/z 376.2 [M+H]⁺.

To a solution of (S)-3-(((1-oxo-2-(2-oxoazepan-3-yl)isoindolin-4-yl)oxy)methyl) benzonitrile (200 mg, 0.48 mmol) in fluorobenzene/DMSO (15mL/2 mL) at RT was added Dess-Martin periodinane (508 mg, 1.2 mmol). Themixture was heated to 80° C. overnight cooled to RT, and 20 mL of sat.sodium thiosulfate solution was added, and the mixture was extractedwith DCM. Workup provided the crude product which was washed withtert-butyl methyl ether to afford(S)-3-(((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzonitrile (120 mg, 58% yield) as a white solid. MS (ESI) m/z 390.1[M+H]⁺.

To a solution of(S)-3-(((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzonitrile(130 mg, 0.334 mmol) in THF (8 mL) at RT was added di-tert-butyldicarbonate (146 mg, 0.668 mmol) and Raney Ni (60 mg). After degassingand purging with H₂, the mixture was stirred at RT overnight. Thesuspension was filtered through a Celite pad. The filtrate wasconcentrated and purified by prep-TLC (EtOAc) to give (S)-tert-butyl3-(((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate as a white solid (150 mg, 59%).

To a solution of (S)-tert-butyl3-(((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)oxy) methyl)benzylcarbamate (75 mg, 0.152 mmol) in DCM (2 mL) at RT was added TFA (1mL). The mixture was stirred at RT for 30 min. The solvent wasevaporated, and the residue was lyophilized to give Compound 9 (40 mg,66% yield) as a white solid. MS (ESI) m/z 394.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 10.73 (s, 1H), 8.18 (s, 3H), 7.58-7.43 (m, 5H), 7.34 (d,J=7.2 Hz, 2H), 5.28-5.23 (m, 3H), 4.80 (m, 2H), 4.10-4.07 (m, 2H),3.08-3.06 (m, 1H), 2.60-2.55 (m, 1H), 2.32-2.29 (m, 1H), 2.12-1.99 (m,2H), 1.80-1.77 (m, 1H).

Example 10 Compound 10:(S)-3-(4-{[m-(Morpholinomethyl)phenyl]methoxy}-2-isoindolinoyl)-2,7-azepanedione

To a solution of (S)-4-hydroxy-2-(2-oxoazepan-3-yl)isoindolin-1-one (160mg, 0.615 mmol), 1,3-phenylenedimethanol (170 mg, 1.23 mmol) andtriphenylphosphine (402 mg, 1.538 mmol) in THF (8 mL), was added DEAD(268 mg, 1.53 mmol) at RT. The mixture was stirred at RT for 30 min. Thesolvent was evaporated, and the residue was purified by prep-TLC(DCM/MeOH, 100:1 to 30:1) to give(S)-4-((3-(hydroxymethyl)benzyl)oxy)-2-(2-oxoazepan-3-yl)isoindolin-1-one(156 mg, 59% yield) as a white solid. MS (ESI) m/z 381.2 [M+H]⁺.

To a solution of(S)-4-((3-(hydroxymethyl)benzyl)oxy)-2-(2-oxoazepan-3-yl)isoindolin-1-one (138 mg, 0.363 mmol) in fluorobenzene/DMSO (4 mL/1 mL)at RT was added Dess-Martin periodinane (462 mg, 1.09 mmol). Afterstirring at 80° C. overnight, the mixture was cooled to RT, and 20 mL ofsat. sodium thiosulfate solution was added followed, and the mixture wasextracted with DCM. Workup provided the crude product which was washedwith tert-butyl methyl ether to afford(S)-3-((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzaldehyde(85 mg, 60% yield) as a white solid. MS (ESI) m/z 391.2 [M+H]⁺.

To a solution of(S)-3-(((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzaldehyde (80 mg, 0.204 mmol) and morpholine (36 mg, 0.408 mmol) inDCM (4 mL) at RT was added NaBH(OAc)₃ (87 mg, 0.408 mmol). The mixturewas stirred overnight. The solvent was evaporated, and the residue waspurified by prep-TLC using DCM/MeOH (10:1) to give Compound 10 (30.5 mg,32% yield) as a white solid. MS (ESI) m/z 464.2[M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 10.73 (s, 1H), 7.49-7.27 (m, 7H), 5.27-5.22 (m, 3H), 4.47 (s,2H), 3.56 (s, 4H), 3.48 (s, 2H), 3.12-3.05 (m, 1H), 2.58 (d, J=16.8 Hz,1H), 2.34 (s, 5H), 2.12-2.06 (m, 1H), 2.04-1.99 (m, 1H), 1.82-1.78 (m,1H).

Example 11 Compound 11:(S)-3-(4-{[p-(Morpholinomethyl)phenyl]methoxy}-3-oxo-2H-isoindol-2-oyl)-2,7-azepanedione

To a solution of 3-methoxyphthalic acid (3.0 g, 15.306 mmol) in THF (24mL) at RT was added acetic anhydride (10 mL). The mixture was stirred at80° C. for 3 hrs. The solvent was evaporated to give4-methoxyisobenzofuran-1,3-dione (2.72 g, quant. yield) as a whitesolid. MS (ESI) m/z=178.9 [M+H]⁺.

To a solution of (S)-3-aminoazepan-2-one (1.96 g, 15.28 mmol) inAcOH/ACN (28 mL/20 mL) at RT was added 4-methoxyisobenzofuran-1,3-dione(2.71 g, 15.28 mmol). The mixture was stirred at 85° C. overnight thencooled to RT. Sodium acetate (3.13 g, 38.20 mmol) was added followed byAcOH (12 mL). The mixture was stirred at 85° C. overnight. The solventwas evaporated then the residue was diluted with water (30 mL) andstirred at RT for 30 min. The resulting suspension was filtered and thefilter cake was washed with EtOAc to give(S)-4-methoxy-2-(2-oxoazepan-3-yl)isoindoline-1,3-dione (2.154 g, 49%yield) as a white solid. MS (ESI) m/z=289.1 [M+H]⁺.

To a solution of (S)-4-methoxy-2-(2-oxoazepan-3-yl)isoindoline-1,3-dione(2.1 g, 7.292 mmol) in DCM (40 mL) at 0° C. was added tribromoborane(3.4 mL) in DCM (10 mL) dropwise. After stirring at RT for 3 hrs, themixture was diluted with ice-water and extracted with DCM. The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated to give the crude product which was washedwith EtOAc to afford(S)-4-hydroxy-2-(2-oxoazepan-3-yl)isoindoline-1,3-dione (1 g, 50% yield)as a light yellow solid. MS (ESI) m/z=275.0 [M+H]⁺.

To a solution of (S)-4-hydroxy-2-(2-oxoazepan-3-yl)isoindoline-1,3-dione(300 mg, 1.095 mmol), 1,4-phenylenedimethanol (272 mg, 1.971 mmol) andtriphenylphosphine (574 mg, 2.190 mmol) in THF (5 mL) at 0° C. was addedDEAD (381 mg, 2.19 mmol). The mixture was stirred at RT overnight. Thesolvent was evaporated and the crude product was purified by silica gelchromatography using EtOAc/petroleum ether from 20% to 96% to give(S)-4-((4-(hydroxymethyl)benzyl)oxy)-2-(2-oxoazepan-3-yl)isoindoline-1,3-dione (168 mg, 39%yield) as a white solid. MS (ESI) m/z=395.1 [M+H]⁺.

To a solution of(S)-4-((4-(hydroxymethyl)benzyl)oxy)-2-(2-oxoazepan-3-yl)isoindoline-1,3-dione(140 mg, 0.355 mmol) in 1,2-dichloroethane/DMSO (12 mL/2 mL) at RT wasadded Dess-Martin reagent (753 mg, 1.775 mmol). The mixture was stirredat 80° C. overnight. The mixture was cooled to RT and filtered, and thefiltrate was quenched with sat. sodium thiosulfate solution (15 mL).After stirring for 10 min, the mixture was extracted with DCM. Workupand purification with EtOAc/petroleum ether from 20% to 96% to afford(S)-4-(((2-(2,7-dioxoazepan-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)methyl)benzaldehyde(95 mg, 54% yield) as a yellow solid.

To a solution of(S)-4-(((2-(2,7-dioxoazepan-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)methyl)benzaldehyde(75 mg, 0.1847 mmol) in DCM (3 mL) at RT was added morpholine (32 mg,0.3694 mmol) and sodium triacetoxyborohydride (78 mg, 0.3694 mmol) andthe mixture stirred overnight. The solvent was evaporated and the crudeproduct was purified by prep-TLC using DCM/MeOH (10:1) to give Compound11 (42 mg, 48% yield) as a white solid. MS (ESI) m/z=477.8 [M+H]⁺. ¹HNMR (DMSO-d₆, 400 MHz) δ: 10.84 (s, 1H), 7.82-7.35 (m, 7H), 5.35 (s,2H), 5.19-5.15 (m, 1H), 3.60-3.50 (m, 4H), 3.50-3.40 (m, 2H), 3.14-3.07(m, 1H), 2.70-2.60 (m, 1H), 2.35 (s, 4H), 2.19-1.87 (m, 4H).

Example 12 Compound 12:(S)-3-(4-{[p-(Morpholinomethyl)phenyl]methoxy}-2-isoindolinoyl)-2,5-pyrrolidinedione

To a stirred solution of(S)-4-amino-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid (2.0 g,8.6 mmol) in THF (10 mL) and MeOH (10 mL) at 0° C. was added(trimethylsilyl)diazomethane solution (2 M in hexane, 6.5 mL) dropwise.The mixture was stirred at 0° C. for 1 hour then concentrated to give(5)-methyl 4-amino-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (crude)as a colorless oil.

To a stirred solution of (5)-methyl4-amino-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (8.6 mmol) in DCM(6 mL) at RT was added TFA (3 mL). After stirring overnight, the mixturewas concentrated to give (5)-methyl 2,4-diamino-4-oxobutanoate, whichwas used directly for the next step.

To a solution of (5)-methyl 2,4-diamino-4-oxobutanoate (8.6 mmol) andmethyl 2-(bromomethyl)-3-methoxybenzoate (2.2 g, 8.6 mmol) in DMF (20mL) was added TEA (3.6 mL). After stirring at 50° C. for 5 hrs, themixture was diluted with water and extracted with EtOAc. Workup andpurification with EtOAc/pet. ether (20% to 80%) provided (9-methyl4-amino-2-(4-methoxy-1-oxoisoindolin-2-yl)-4-oxobutanoate (1.2 g, 48%yield) as a yellow solid. MS (ESI) m/z=293.0 [M+H]⁺.

To a solution of (9-methyl4-amino-2-(4-methoxy-1-oxoisoindolin-2-yl)-4-oxobutanoate (1.2 g, 4.1mmol) in DCM (12 mL) at 0° C. was added boron tribromide (2.3 mL)dropwise. The mixture was stirred at RT for 2 hrs and quenched by waterand MeOH. The solvent was evaporated, and the residue was purified bysilica gel chromatography (DCM/MeOH, 20:1) to give(S)-4-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-4-oxobutanoic acid (3 g,crude) as a yellow solid. MS (ESI) m/z=265.0 [M+H]⁺.

To a solution of(S)-4-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-4-oxobutanoic acid (3 gcrude) in THF (15 mL) and MeOH (15 mL) was added(trimethylsilyl)diazomethane solution (2 M in hexane, 6.8 mL) at 0° C.dropwise. The mixture was stirred at 0° C. for 1.5 hrs and concentrated.The residue was purified by silica gel chromatography (DCM/MeOH, 10:1)to give (S)-methyl4-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-4-oxobutanoate (470 mg, 43%yield) as a white solid. MS (ESI) m/z=279.0 [M+H]⁺.

To a solution of (9-methyl4-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-4-oxobutanoate (300 mg, 1.08mmol), (4-(morpholinomethyl)phenyl)methanol (335 mg, 1.62 mmol) andtriphenylphosphine (567 mg, 2.16 mmol in THF, 8 mL) at 0° C. was addedDEAD (376 mg, 2.16 mmol) and the mixture was stirred at RT overnight.The solvent was evaporated, and the residue was purified by prep-TLC(DCM/MeOH, 10:1) to give(9-methyl-4-amino-2-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-4-oxobutanoate(150 mg, 30% yield) as a white solid. MS (ESI) m/z=468.1 [M+H]⁺.

To a solution of(9-methyl-4-amino-2-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-4-oxobutanoate(100 mg, 0.21 mmol) in THF (6 mL) at RT was added lithium hydroxide (11mg, 0.42 mmol). The mixture was stirred for 3 hrs then diluted withwater and adjusted pH to 3 with 1 N HCl. Workup and purification with byprep-TLC (DCM/MeOH, 10:1) to afford Compound 12 (13 mg, 14% yield) as ayellow solid. MS (ESI) m/z=453.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ11.49 (brs, 1H), 7.51-7.44 (m, 3H), 7.34-7.30 (m, 4H), 5.27 (t, J=8.0Hz, 1H), 5.23 (s, 2H), 4.61 (d, J=17.2 Hz, 1H), 4.27 (d, J=17.2 Hz, 1H),3.57 (t, J=4.0 Hz, 4H), 3.46 (s, 2H), 2.94 (d, J=7.6 Hz, 2H), 2.34 (s,4H).

Example 13 Compound 13:(S)-3-(4-{[p-({3-[3-(p-{5-Methyl-4-[m-(tert-butylaminosulfonyl)phenylamino]-2-pyrimidinylamino}phenoxy)propyl]ureido}methyl)phenyl]methoxy}-2-isoindolinoyl)-2,7-azepanedione

To a solution of tert-butyl(3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)carbamate(100 mg, 0.171 mmol) in dry DCM (8 mL) at 0° C. was added TFA (2 mL).The reaction was stirred at RT for 16 hrs. The solvent was evaporated,and the residue was dried to give the amine TFA salt (100 mg, crude).The amine TFA salt was dissolved in THF (5 mL) and TEA (34.5 mg, 0.342mmol) was added at RT followed by 4-nitrobenzyl chloroformate (34.2 mg,0.171 mmol). The mixture was stirred for 1 hour. The solvent wasevaporated to give 4-nitrophenyl(3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)carbamate (30 mg, crude) which was used directly for the next step. MS(ESI) m/z 650.2[M+H]⁺.

To a solution of (S)-tert-butyl4-(((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate (23 mg, 0.046 mmol) in DCM (4 mL) at RT wasadded TFA (1 mL). The solvent was evaporated, and the residue was driedto give the amine TFA salt (30 mg, crude) as a yellow gum. The amine TFAsalt was dissolved in THF (5 mL) and TEA (10 mg, 0.092 mmol) was addedat RT followed by a suspension of 4-nitrophenyl(3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)carbamate(30 mg, 0.046 mmol) in THF (1 mL). The reaction was stirred at 60° C.for 3 hrs. The solvent was evaporated, and the residue was purified bysilica gel chromatography eluting with MeOH/DCM from 0% to 9% to giveCompound 13 (22.3 mg, 53% yield) as a white solid. MS (ESI) m/z903.7[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H), 8.82 (s, 1H),8.57 (s, 1H), 8.15-8.12 (m, 2H), 7.89 (s, 1H), 7.59 (s, 1H), 7.54-7.41(m, 7H), 7.31-7.25 (m, 4H), 6.79 (d, J=8.8 Hz, 2H), 6.37 (t, J=6.0 Hz,1H), 6.06 (t, J=5.2 Hz, 1H), 5.23-5.19 (m, 3H), 4.45 (s, 2H), 4.21 (d,J=6.4 Hz, 2H), 3.91 (t, J=5.6 Hz, 2H), 3.19-3.15 (m, 2H), 3.09-3.02 (m,1H), 2.58-2.54 (m, 1H), 2.35-2.31 (m, 1H), 2.11 (s, 3H), 2.04-1.97 (m,1H), 1.82-1.78 (m, 3H), 1.12 (s, 9H).

Example 14 Compound 14:(S)-3-(4-{[p-(Morpholinomethyl)phenoxy]methyl}-2-isoindolinoyl)-2,7-azepanedione

To a solution of(S)-1-oxo-2-(2-oxoazepan-3-yl)isoindoline-4-carbaldehyde (910 mg, 3.35mmol) in THF (25 mL) at RT was added sodium borohydride (254 mg, 6.70mmol). The mixture was stirred for 2 hrs. The reaction was concentratedto give the crude product which was purified by silica gelchromatography eluting with MeOH/DCM (1:10) to give(S)-4-(hydroxymethyl)-2-(2-oxoazepan-3-yl) isoindolin-1-one (539 mg, 59%yield) as a white solid. MS (ESI) m/z=275.1[M+H]⁺.

To a solution of (S)-4-(hydroxymethyl)-2-(2-oxoazepan-3-yl)isoindolin-1-one (539 mg, 1.97 mmol), 4-hydroxybenzaldehyde (288 mg,2.36 mmol) and triphenylphosphine (1.03 g, 3.93 mmol) in THF (30 mL) at0° C. was added DEAD (685 mg, 3.93 mmol). The mixture was stirred for 15min then warmed to RT and stirred overnight. The solvent was evaporatedto give the crude product, which was purified by silica gelchromatography eluting with MeOH/DCM from 0% to 5% to afford(S)-4-((1-oxo-2-(2-oxoazepan-3-yl)isoindolin-4-yl)methoxy)benzaldehyde(520 mg, 70% yield) as a white solid. MS (ESI) m/z 379.1 [M+H]⁺.

To a solution of (S)-4-((1-oxo-2-(2-oxoazepan-3-yl)isoindolin-4-yl)methoxy) benzaldehyde (520 mg, 1.38 mmol) in fluorobenzene/DMSO (24 mL/4mL, 1 drop water in DMSO) was added Dess-Martin reagent (1.46 g, 3.44mmol). The suspension was heated at 80° C. for 18 hrs. The suspensionwas cooled to RT then added to sat. aqueous sodium thiosulfate solution(20 mL) at 0° C. and stirred for 5 min then extracted with DCM. Workupand purification with EtOAc/petroleum ether from 20% to 96% to give(S)-4-((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)methoxy)benzaldehyde(174.2 mg, 32% yield) a white solid. MS (ESI) m/z 393.1 [M+H]⁺.

To a solution of (S)-4-((2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)methoxy) benzaldehyde (100 mg, 0.255 mmol) in THF (5 mL) at RT was addedmorpholine (88 mg, 1.02 mmol), followed by sodium cyanoborohydride (64mg, 1.02 mmol). The mixture was stirred for 2 hrs. The solvent wasevaporated, and the residue was purified by prep-HPLC as previouslydescribed to give Compound 14 (22.1 mg, 19% yield) as a white solid. MS(ESI) m/z=498.1 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz) δ: 10.76 (s, 1H),7.73-7.71 (m, 2H), 7.55 (t, J=7.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.01(d, J=8.4 Hz, 2H), 5.25 (s, 2H), 4.63 (s, 2H), 3.55 (s, 4H), 3.36 (s,2H), 3.13-3.06 (m, 1H), 2.59-2.55 (m, 1H), 2.32 (s, 4H), 2.17-1.97 (m,3H), 1.86-1.76 (m, 1H).

Example 15 Compound 15:(S)-3-(5-{[p-(Morpholinomethyl)phenyl]methoxy}-2-isoindolinoyl)-2,7-azepanedione

To a solution of methyl 4-methoxy-2-methylbenzoate (10 g, 55.56 mmol) incarbon tetrachloride (150 mL) at RT was added NBS (10 g, 55.57 mmol) and2,2′-azobis(2-methylpropionitrile) (4.0 mg, 9.43 mmol). The mixture wasstirred at reflux 6 hrs. The solvent was evaporated to give the crudeproduct which was purified by silica gel chromatography (EtOAc/petroleumether, 1:20 to 1:5) to give methyl 2-(bromomethyl)-4-methoxybenzoate(13.6 g, 94% yield) as a white solid.

To a solution of (S)-3-aminoazepan-2-one (1.6 g, 12.4 mmol) in DMF (16mL) at RT was added TEA (2.9 mL, 20.6 mmol) and methyl2-(bromomethyl)-4-methoxybenzoate (2.7 g, 10.3 mmol) in 4 mL DMF. Themixture was stirred at 85° C. overnight. The solvent was evaporated andthe crude product was purified by silica gel chromatography (DCM/MeOH,50:1) to give (5)-5-methoxy-2-(2-oxoazepan-3-yl)isoindolin-1-one (1.39g, 49% yield) as a white solid. MS (ESI) m/z 275.0 [M+H]⁺.

To a solution of (S)-5-methoxy-2-(2-oxoazepan-3-yl)isoindolin-1-one (1.0g, 3.65 mmol) in DCM (12 mL) at 0° C. was added boron tribromide (2.0mL, 21.89 mmol, in 4 mL DCM) dropwise. The mixture was stirred at thistemperature for 30 min then warmed to RT for 2 hrs and quenched by waterand MeOH. The solvent was evaporated, and the residue was purified bysilica gel chromatography (DCM/MeOH, 20:1) to give(5)-5-hydroxy-2-(2-oxoazepan-3-yl)isoindolin-1-one (1.7 g crude) as awhite solid. MS (ESI) m/z 261.0 [M+H]⁺.

To a solution of (S)-5-hydroxy-2-(2-oxoazepan-3-yl)isoindolin-1-one (500mg, 1.92 mmol), 1,4-phenylenedimethanol (1.0 g, 7.68 mmol) andtriphenylphosphine (2.0 g, 7.68 mmol) in THF (2 mL) at RT was added DEAD(1.3 mg, 7.68 mmol) at RT. The mixture was stirred for 2 hrs. Thesolvent was evaporated, and the residue was purified by silica gelchromatography (DCM/MeOH, 50:1 to 20:1) to give(S)-5-((4-(hydroxymethyl)benzyl)oxy)-2-(2-oxoazepan-3-yl)isoindolin-1-one(90 mg, 12% yield) as a white solid. MS (ESI) m/z 381.1 [M+H]⁺.

To a solution of(S)-5-((4-(hydroxymethyl)benzyl)oxy)-2-(2-oxoazepan-3-yl)isoindolin-1-one(60 mg, 0.157 mmol) in fluorobenzene/DMSO (6.0 mL/1.5 mL) at RT wasadded Dess-Martin periodinane (268 mg, 0.631 mmol). After stirring at80° C. overnight, the mixture was cooled to RT then 20 mL of sat. sodiumthiosulfate solution was added, and the mixture was stirred at RT for 5min. Workup and purification with by prep-TLC using hexanes/EtOAc (1:1)provided(S)-4-(((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)benzaldehyde(15 mg, 16% yield) as a white solid. MS (ESI) m/z 393.0 [M+H]⁺.

To a solution of(S)-4-(((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)benzaldehyde (15 mg, 0.038 mmol) and morpholine (7 mg, 0.076mmol) in DCM at RT was added sodium triacetoxyborohydride (16 mg, 0.076mmol). The mixture was stirred for 28 hrs. The solvent was evaporated,and the crude product was purified by prep-TLC using DCM/MeOH (10:1) togive Compound 15 (6.5 mg, 38% yield) as a white solid. MS (ESI) m/z464.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.71 (s, 1H), 7.64 (d, J=8.4Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.27 (s, 1H),7.13 (d, J=8.8 Hz, 1H), 5.23-5.19 (m, 3H), 4.48-4.47 (m, 2H), 3.58-3.56(m, 4H), 3.47 (s, 2H), 3.08-3.06 (m, 1H), 2.60-2.51 (m, 1H), 2.35 (s,4H), 2.27-2.24 (m, 1H), 2.10-2.00 (m, 2H), 1.80-1.77 (m, 1H).

Example 16 Compound 16:(S)-6-(4-{[p-(Morpholinomethyl)phenyl]methoxy}-2-isoindolinoyl)-1,4-oxazepane-3,5-dione

To a solution of 3-hydroxy-2-methylbenzoic acid (20 g, 0.13 mmol) inMeOH (240 mL) at 0° C. was added thionyl chloride dropwise, then themixture was stirred at reflux for 3 hrs. The solvent was evaporated, andthe residue was purified by silica gel chromatography (petroleumether/EtOAc, 20:1 to 5:1) to give methyl 3-hydroxy-2-methylbenzoate(18.7 g, 86% yield) as a yellow solid.

To a solution of methyl 3-hydroxy-2-methylbenzoate (18.7 g, 0.11 mol)and imidazole (19.0 g, 0.25 mol) in DMF (28 mL) at RT was addedtert-butyldimethylsilyl chloride (20.4 g, 0.12 mol). After stirring at60° C. for 3 hrs, the mixture was cooled to RT and extracted withtert-butyl methyl ether. The combined organic layers were dried overanhydrous Na₂SO₄, filtered, and concentrated to give methyl3-((tert-butyldimethylsilyl)oxy)-2-methylbenzoate (32 g crude) as ayellow solid which was used in the next step without furtherpurification.

To a solution of 3-((tert-butyldimethylsilyl)oxy)-2-methylbenzoate (5.0g, 17.8 mmol) in carbon tetrachloride (30 mL) at RT was added NBS (4.7g, 26.8 mmol) and 2,2′-azobis(2-methylpropionitrile) (1.1 g, 7.1 mmol).The suspension was stirred at reflux for 5 hrs. The solvent wasevaporated, and the residue was purified by silica gel chromatography(petroleum ether/EtOAc, 100:1 to 50:1) to give methyl2-(bromomethyl)-3-((tert-butyldimethylsilyl) oxy)benzoate (5.8 g, 90%yield) as a yellow oil.

To a solution of methyl 2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)benzoate (490 mg, 1.4 mmol) in DMF (6 mL) at RT was added TEA (0.4 mL,2.8 mmol) and (S)-6-amino-1,4-oxazepan-5-one (200 mg, 1.5 mmol, in 2 mLof DMF). The mixture was stirred at RT for 4 hrs, then heated to 80° C.overnight. The mixture was concentrated, and the residue was dilutedwith THF (10 mL). TBAF (200 mg, 0.76 mmol) was added, and the mixturewas stirred at reflux for 2 hrs. The solvent was evaporated and theresidue purified by silica gel chromatography (DCM/MeOH, 50:1 to 20:1)to give (S)-6-(4-hydroxy-1-oxoisoindolin-2-yl)-1,4-oxazepan-5-one (183mg, 50% yield) as a white solid. MS (ESI) m/z 263.0 [M+H]⁺.

To a solution of(S)-6-(4-hydroxy-1-oxoisoindolin-2-yl)-1,4-oxazepan-5-one (230 mg, 0.87mmol), 1,4-phenylenedimethanol (182 mg, 1.31 mmol) andtriphenylphosphine (568 mg, 2.17 mmol) in THF (2.5 mL) at RT was addedDEAD (377 mg, 2.17 mmol). The mixture was stirred at RT for 3 hrs. Thesolvent was evaporated and the crude product was purified by silica gelchromatography (DCM/MeOH, 100:1 to 20:1) to give(S)-6-(4-((4-(hydroxymethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-1,4-oxazepan-5-one(110 mg, 33% yield) as a white solid. MS (ESI) m/z 383.1 [M+H]⁺.

To a solution of(S)-6-(4-((4-(hydroxymethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-1,4-oxazepan-5-one(110 mg, 0.288 mmol) in ACN/DMSO (8 mL/2 mL) at RT was added Dess-Martinperiodinane (732 mg, 1.72 mmol). The mixture was stirred at 80° C. for 4hrs, then cooled to RT, and 20 mL of a sat. sodium thiosulfate solutionwas added followed by stirring for 5 min. The mixture was extracted withDCM. Workup and purification with DCM then DCM/EtOAc, 5:1 to 1:1 to give(S)-4-(((2-(3,5-dioxo-1,4-oxazepan-6-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzaldehyde (58 mg, 51% yield) as a white solid. MS (ESI)m/z 395.0 [M+H]⁺.

To a solution of(S)-4-(((2-(3,5-dioxo-1,4-oxazepan-6-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzaldehyde(58 mg, 0.147 mmol) and morpholine (26 mg, 0.294 mmol) in DCM (1.5 mL)at RT was added sodium triacetoxyborohydride (64 mg, 0.294 mmol). Themixture was stirred at RT for 4 hrs then concentrated. The crude productwas purified by prep-TLC using DCM/MeOH (10:1) to give Compound 16 (19mg, 20% yield) as a white solid. MS (ESI) m/z 465.9 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.48-7.44 (m, 3H), 7.35-7.32 (m, 4H),5.67-5.66 (m, 1H), 5.24 (s, 2H), 4.71 (d, J=17.2 Hz, 1H), 4.55 (d,J=10.4 Hz, 2H), 4.40-4.35 (m, 2H), 4.06-4.05 (m, 1H), 3.57-3.55 (m, 4H),3.47 (s, 2H), 2.35 (s, 4H).

Example 17 Compound 17:3-(4-{[p-({2-[3-(p-{5-Methyl-4-[m-(tert-butylaminosulfonyl)phenylamino]-2-pyrimidinylamino}phenoxy)propylamino]acetylamino}methyl)phenyl]methoxy}-2-isoindolinoyl)-2,6-piperidinedione

To a solution of 3-hydroxy-2-methylbenzoic acid (20 g, 0.13 mol) in MeOH(240 mL) at 0° C. was added thionyl chloride (30 mL, 0.41 mol) dropwise.The mixture was stirred at reflux for 3 hrs. The solvent was evaporated,and the residue was purified by silica gel chromatography usingpetroleum ether/EtOAc (20:1 to 5:1) to give methyl3-hydroxy-2-methylbenzoate (18.7 g, 86% yield) as a yellow solid.

To a solution of methyl 3-hydroxy-2-methylbenzoate (18.7 g, 0.11 mol)and imidazole (19.0 g, 0.25 mol) in DMF (28 mL) at RT,tert-butyldimethylsilyl chloride (20.4 g, 0.12 mol) was added. Afterstirring at 60° C. for 3 hrs, the mixture was cooled to RT and extractedwith tert-butyl methyl ether. The combined organic layers were driedover anhydrous Na₂SO₄, filtered, and concentrated to give methyl3-((tert-butyldimethylsilyl)oxy)-2-methylbenzoate (32 g crude) as ayellow solid which was used in the next step without furtherpurification.

To a solution of methyl3-((tert-butyldimethylsilyl)oxy)-2-methylbenzoate (3.0 g, 10.7 mmol) incarbon tetrachloride (22 mL) at RT was added NBS (2.9 g, 16.0 mmol) and2,2′-azobis(2-methylpropionitrile) (701 mg, 4.3 mmol). The mixture wasstirred at 80° C. for 5 hrs. The solvent was evaporated to give thecrude product which was purified by silica gel chromatography (petroleumether/EtOAc, 30:1) to give methyl2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)benzoate (3.7 g 97%) asa yellow oil.

To a solution of methyl 2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)benzoate (1.0 g, 2.77 mmol) and TEA (0.8 mL, 5.54 mmol) in DMF (6mL) at RT was added tert-butyl 2,5-diamino-5-oxopentanoate (670 mg, 3.32mmol) in DMF (4 mL). The mixture was stirred for 2 hrs then heated to80° C. and stirred overnight. The solvent was evaporated to give thecrude product which was purified by silica gel chromatography (DCM/MeOH,100:1 to 50:1) to afford tert-butyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (820 mg, 88%yield) as a white solid. MS (ESI) m/z 279.0 [M+H−56]⁺.

To a solution of tert-butyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (450 mg, 1.34mmol), 4-(hydroxymethyl)benzonitrile (360 mg, 2.69 mmol) andtriphenylphosphine (1.4 g, 5.36 mmol) in THF (2 mL) at RT was added DEAD(932 mg, 5.36 mmol) dropwise. The mixture was stirred at RT for 4 h. Thesolvent was evaporated and the crude product was purified by silica gelchromatography (DCM/MeOH, 100:1 to 20:1) to give tert-butyl5-amino-4-(4-((4-cyanobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(290 mg, 39% yield) as a white solid. MS (ESI) m/z 394.0 [M+H−56]⁺.

To a solution of tert-butyl5-amino-4-(4-((4-cyanobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(200 mg, 0.45 mmol) in DCM (6 mL) at RT was added TFA (1.5 mL). Themixture was stirred at RT for 5 hrs then concentrated to give5-amino-4-(4-((4-cyanobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoicacid TFA salt (250 mg crude) as a white solid, which was used for thenext step without further purification. MS (ESI) m/z 394.0 [M+H]⁺.

To a solution of5-amino-4-(4-((4-cyanobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoicacid TFA salt (250 mg, 0.45 mmol) in ACN (8 mL) at RT was added CDI (291mg, 1.80 mmol). The mixture was stirred at 95° C. for 6 hrs. The solventwas evaporated to give the crude product which was purified by silicagel chromatography (DCM/MeOH, 100:1 to 50:1) to give4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzonitrile (130 mg 77%) as a white solid. MS (ESI) m/z 376.0[M+H]⁺.

To a solution of4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzonitrile (130 mg, 0.346 mmol) and di-tert-butyl dicarbonate(0.16 mL, 0.693 mmol) in DCM (4 mL) and THF (4 mL) at RT was addedRaney-Ni (80 mg). The mixture was stirred at RT for 16 hrs under H₂ thenMeOH (4 mL) was added, and the mixture was heated to 80° C. for 5 hrs.After cooling to RT, the suspension was filtrated through a Celite padand the filtrate was concentrated to give the crude product, which waspurified by silica gel chromatography using DCM/MeOH (50:1 to 20:1) toafford tert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate(100 mg, 60% yield) as a white solid. MS (ESI) m/z 380.0 [M+H−100]⁺.

To a solution of tert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate(100 mg, 0.208 mmol) in DCM (4 mL) at RT was added TFA (2 mL). Themixture was stirred at RT overnight. The solvent was evaporated to give3-(4-((4-(aminomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneTFA salt (80 mg crude) as a white solid, which was used for the nextstep without further purification. MS (ESI) m/z 380.0 [M+H]⁺.

To a solution of tert-butyl 2-((3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)amino) acetate(70 mg, 0.117 mmol) in DCM (4 mL) at RT was added TFA (1.5 mL) and themixture was stirred at RT overnight. The solvent was evaporated, and theresidue was dissolved in DMF (4 mL) then3-(4-((4-(aminomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(80 mg, 0.162 mmol), DIEA (63 mg, 0.486 mmol), HOBt (33 mg, 0.243 mmol)and EDAC.HCl (47 mg, 0.243 mmol) were added. The mixture was stirred atRT for 18 hrs. The solvent was evaporated and the crude product waspurified by prep-HPLC as previously described to give Compound 17 (11.3mg, 10% yield) as a white solid. MS (ESI) m/z 904.3 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 10.98 (s, 1H), 8.79 (s, 1H), 8.54 (s, 1H), 8.32 (t,J=6.0 Hz, 1H), 8.15 (s, 2H), 7.89 (s, 1H), 7.58-7.40 (m, 9H), 7.32-7.26(m, 4H), 6.78 (d, J=8.8 Hz, 2H), 5.19 (s, 2H), 5.12-5.07 (m, 1H),4.41-4.21 (m, 4H), 3.96 (t, J=6.4 Hz, 2H), 3.16 (s, 2H), 2.93-2.86 (m,1H), 2.65-2.62 (m, 2H), 2.59-2.51 (m, 1H), 2.46-2.41 (m, 1H), 2.11 (s,3H), 2.09-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.12 (s, 9H).

Example 18 Compound 18:(S)-3-(6-Fluoro-4-{[p-({3-[3-(p-{5-methyl-4-[m-(tert-butylaminosulfonyl)phenylamino]-2-pyrimidinylamino}phenoxy)propyl]ureido}methyl)phenyl]methoxy}-2-isoindolinoyl)-2,6-piperidinedione

To a solution of methyl 5-fluoro-3-hydroxy-2-methylbenzoate (3.2 g, 17.4mmol) and imidazole (2.9 g, 43.5 mmol) in DMF (6 mL) at RT was addedtert-butyldimethylsilyl chloride (3.1 g, 20.8 mmol). The mixture wasstirred at 60° C. for 1 hr, cooled to RT and extracted with tert-butylmethyl ether, dried over anhydrous Na₂SO₄, concentrated to give methyl3-((tert-butyldimethylsilyl)oxy)-5-fluoro-2-methylbenzoate (5.2 g crude)as a yellow oil, which was used for the next step without furtherpurification.

To a solution of methyl3-((tert-butyldimethylsilyl)oxy)-5-fluoro-2-methylbenzoate (3.2 g, 10.7mmol) in carbon tetrachloride (30 mL) at RT was added NBS (2.9 g, 16.1mmol) and 2,2′-azobis(2-methylpropionitrile) (700 mg, 4.3 mmol). Themixture was stirred at 80° C. for 6 h. The solvent was evaporated togive the crude product which was purified by silica gel chromatography(petroleum ether/EtOAc, 10:1) to give methyl2-(bromomethyl)-3-((tert-butyldimethylsilyl) oxy)-5-fluorobenzoate (4.0g, quant. yield) as a yellow oil.

To a solution of methyl2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)-5-fluorobenzoate (1.0g, 2.66 mmol) and TEA (0.7 mL, 5.32 mmol) in DMF (6 mL) at RT was added(S)-tert-butyl 4,5-diamino-5-oxopentanoate (696 mg, 2.92 mmol) in 4 mLDMF. The mixture was stirred for 2 h then heated to 80° C. overnight.The solvent was evaporated to give the crude product which was purifiedby silica gel chromatography (DCM/MeOH, 50:1 to 20:1) to give(S)-tert-butyl5-amino-4-(6-fluoro-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.0g crude) as a white solid. MS (ESI) m/z 297.0 [M+H−56]⁺.

To a solution of (S)-tert-butyl5-amino-4-(6-fluoro-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (500mg, 1.42 mmol), 4-(hydroxymethyl)benzonitrile (283 mg, 2.13 mmol) andtriphenylphosphine (930 mg, 3.55 mmol) in THF (4 mL) at RT was addedDEAD (617 mg, 3.55 mmol). The mixture was stirred at RT for 2 hrs. Thesolvent was evaporated, and the residue was purified by silica gelchromatography (DCM/MeOH, 100:1 to 50:1) to give (S)-tert-butyl5-amino-4-(4-((4-cyanobenzyl)oxy)-6-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoate(350 mg, 52% yield) as a yellow solid. MS (ESI) m/z 412.0 [M+H−56]⁺.

To a solution of (S)-tert-butyl5-amino-4-(4-((4-cyanobenzyl)oxy)-6-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoate(350 mg, 0.75 mmol) in DCM (4 mL) at RT was added TFA (4 mL). Themixture was stirred at RT overnight. The solvent was evaporated to give(5)-5-amino-4-(4-(4-cyanobenzyl)oxy)-6-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoicacid (400 mg crude) as a yellow solid, which was used for the next stepwithout further purification. MS (ESI) m/z 412.0 [M+H]⁺.

To a solution of(S)-5-amino-4-(4-((4-cyanobenzyl)oxy)-6-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoicacid (400 mg, 0.75 mmol) in ACN (10 mL) at RT was added CDI (485 mg,2.99 mmol). The mixture was stirred at 95° C. for 3.5 hrs. The solventwas evaporated to give the crude product, which was purified by silicagel chromatography (DCM/MeOH, 100:1 to 50:1) to give(S)-4-(((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)benzonitrile(200 mg 68%) as a white solid. MS (ESI) m/z 394.0 [M+H]⁺.

To a solution of(S)-4-(((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)benzonitrile(200 mg, 0.51 mmol) and di-tert-butyl dicarbonate (166 mg, 0.76 mmol) inTHF (6 mL) at RT was added Raney-Ni (80 mg). The mixture was stirredunder H₂ overnight. The suspension was filtered and the filtrate wasconcentrated and purified by silica gel chromatography (DCM/MeOH, 100:1to 20:1) to give (S)-tert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate(90 mg, 35% yield) as a white solid. MS (ESI) m/z 398.0 [M+H−100]⁺.

To a solution of (S)-tert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate(70 mg, 0.146 mmol) in DCM (2 mL) at RT was added TFA (0.5 mL). Themixture was stirred at RT for 2 hrs. The solvent was evaporated to give(S)-3-(4-((4-(aminomethyl)benzyl)oxy)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione(80 mg crude) as a white solid, which was used for the next step withoutfurther purification. MS (ESI) m/z 398.0 [M+H]⁺.

To a solution of(S)-3-(4-((4-(aminomethyl)benzyl)oxy)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione(80 mg, 0.146 mmol) and TEA (45 mg, 0.438 mmol) in THF at RT was added4-nitrophenyl(3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)carbamate(90 mg, 0.138 mmol). After stirring for 15 min, TEA (103 mg, 1.022 mmol)was added, and the reaction was stirred for 2 hrs. The solvent wasevaporated to give the crude product which was purified by prep-HPLC aspreviously described to afford Compound 18 (60.9 mg, 46% yield) as awhite solid. MS (ESI) m/z 908.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ10.96 (s, 1H), 8.76 (s, 1H), 8.52 (s, 1H), 8.14-8.12 (m, 2H), 7.88 (s,1H), 7.55-7.40 (m, 7H), 7.26-7.24 (m, 3H), 7.11-7.08 (m, 1H), 6.79 (d,J=8.8 Hz, 2H), 6.36 (t, J=5.6 Hz, 1H), 6.04 (t, J=5.6 Hz, 1H), 5.20 (s,2H), 5.11-5.06 (m, 1H), 4.36 (d, J=17.2 Hz, 1H), 4.23-4.19 (m, 3H), 3.91(t, J=6.0 Hz, 2H), 3.19-3.14 (m, 2H), 2.89-2.82 (m, 1H), 2.58-2.50 (m,1H), 2.45-2.40 (m, 1H), 2.11 (s, 3H), 1.99-1.89 (m, 1H), 1.82-1.79 (m,2H), 1.12 (s, 9H).

Example 19 Compound 19:2-[(S)-2,7-Dioxo-3-azepanyl]-4-{[p-(morpholinomethyl)phenyl]methoxy}-1-oxo-5-isoindolinecarbonitrile

To a solution of 3-hydroxy-2-methylbenzoic acid (100.0 g, 660 mmol) indry MeOH (700 mL) at 0° C. was added thionyl chloride (156.0 g, 1316mmol). The reaction was heated to 70° C. for 3 hrs. The reaction wascooled to RT and the solvent was evaporated. The residue was dilutedwith water and extracted with EtOAc. Workup and purification with EtOAcin petroleum ether from 0% to 8% to give methyl3-hydroxy-2-methylbenzoate (102 g, 93% yield) as a white solid.

NBS (53.6 g, 301.2 mmol) was added to a solution of methyl3-hydroxy-2-methylbenzoate (50.0 g, 301.2 mmol) in DCM (800 mL) at −78°C. The mixture was stirred at −78° C. for 1 hour then concentrated. Thecrude product was purified by silica gel chromatography eluting withEtOAc in petroleum ether (from 0% to 8%) to give methyl4-bromo-3-hydroxy-2-methylbenzoate (15.0 g, 21% yield) as a colorlesssolid.

To a solution of methyl 4-bromo-3-hydroxy-2-methylbenzoate (10.0 g,40.82 mmol) in DMF (50 mL) was added zinc cyanide (480 mg, 40.82 mmol)and tetrakis(triphenylphosphine)palladium (240 mg, 2.04 mmol). Themixture was heated to 100° C. for 5 hrs. The reaction was cooled to RTand the solvent was evaporated. The residue was diluted with water andextracted with EtOAc. Workup and purification with EtOAc in petroleumether (from 0% to 15%) to give methyl 4-cyano-3-hydroxy-2-methylbenzoate(2.1 g, 27% yield) as a white solid.

To a solution of methyl 4-cyano-3-hydroxy-2-methylbenzoate (2.1 g, 11.0mmol) and imidazole (1.5 g, 22.0 mmol) in DMF (6 mL) at RT was addedtert-butyldimethylsilyl chloride (1.98 g, 13.2 mmol). After stirring at60° C. for 1 hour, the solution was cooled to RT and extracted withtert-butyl methyl ether, dried over anhydrous Na₂SO₄, filtered,concentrated to give methyl3-((tert-butyldimethylsilyl)oxy)-4-cyano-2-methylbenzoate (3.2 g crude)as a yellow oil, which was used for the next step without furtherpurification.

To a solution of methyl3-((tert-butyldimethylsilyl)oxy)-4-cyano-2-methylbenzoate (3.2 g, 10.5mmol) in carbon tetrachloride (50 mL) at RT was added NBS (2.43 g, 13.64mmol) and 2,2′-azobis(2-methylpropionitrile) (690 mg, 4.2 mmol). Thesuspension was stirred at 80° C. for 5 hrs. The solvent was evaporatedto give the crude product which was purified by silica gelchromatography (petroleum ether/EtOAc, 10:1) to give methyl2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)-4-cyanobenzoate (3.5 g87%) as a colorless oil.

To a solution of methyl2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)-4-cyanobenzoate (2.65g, 6.92 mmol) and TEA (1.39 g, 113.8 mmol) in DMF (20 mL) at RT wasadded (S)-3-aminoazepan-2-one (1.06 g, 8.3 mmol). The mixture wasstirred for 2 hrs then heated to 50° C. overnight. After cooling to RT,tetrabutylammonium fluoride (2.61 g, 8.3 mmol) was added. The mixturewas heated to 50° C. for 1 hour. The solvent was evaporated to give thecrude product which was purified by silica gel chromatography (DCM/MeOH,50:1 to 20:1) to afford(S)-4-hydroxy-1-oxo-2-(2-oxoazepan-3-yl)isoindoline-5-carbonitrile (1.3g, crude) as a yellow solid.

To a solution of(S)-4-hydroxy-1-oxo-2-(2-oxoazepan-3-yl)isoindoline-5-carbonitrile (1.0g, 3.5 mmol), 4-(bromomethyl)benzaldehyde (900 mg, 4.6 mmol) in DMF (515mL) was added K₂CO₃ 970 mg, 7.1 mmol). The mixture was heated to 50° C.for 2 h. The solvent was evaporated to give the crude product, which waspurified by silica gel chromatography (DCM/MeOH, 50:1 to 20:1) to afford(S)-4-((4-formylbenzyl)oxy)-1-oxo-2-(2-oxoazepan-3-yl)isoindoline-5-carbonitrile (600 mg, 42% yield) as a yellow solid. MS(ESI) m/z 404.2 [M+H]⁺.

To a solution of (S)-4-((4-formylbenzyl)oxy)-1-oxo-2-(2-oxoazepan-3-yl)isoindoline-5-carbonitrile (980 mg, 2.44 mmol) in ACN/DMSO (12 mL/2 mL)at RT was added Dess-Martin periodinane (2.6 g, 6.1 mmol). The mixturewas stirred at 80° C. overnight. The mixture was cooled to RT and 100 mLof a sat. sodium thiosulfate solution was added followed by stirring for5 min. The mixture was extracted with DCM. Workup and purification withDCM/ACN, 5:1 to 3:1 provided(S)-2-(2,7-dioxoazepan-3-yl)-4-((4-formylbenzyl)oxy)-1-oxoisoindoline-5-carbonitrile(600 mg, 59% yield) as a white solid. MS (ESI) m/z 418.0 [M+H]⁺.

To a solution of(S)-2-(2,7-dioxoazepan-3-yl)-4-((4-formylbenzyl)oxy)-1-oxoisoindoline-5-carbonitrile(700 mg, 1.68 mmol) and morpholine (292 mg, 3.36 mmol) in DCM (15 mL) atRT was added sodium triacetoxyborohydride (850 mg, 4.2 mmol). Themixture was stirred for 3 hrs then concentrated. The residue waspurified by silica gel chromatography (DCM/ACN, 3:1 to 1:1) to affordCompound 19 (800 mg, 57% yield) as a white solid. MS (ESI) m/z 489.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (s, 1H), 7.91 (d, J=7.6 Hz,1H), 7.54-7.46 (m, 3H), 7.36 (d, J=8.4 Hz, 2H), 5.47 (s, 2H), 5.29-5.25(m, 1H), 4.86 (t, J=2.4 Hz, 2H), 3.58-3.56 (m, 4H), 3.47 (s, 2H),3.14-3.06 (m, 1H), 2.58 (d, J=16.4 Hz, 1H), 2.40-2.34 (m, 5H), 2.13-2.00(m, 2H), 1.83-1.81 (m, 1H).

Example 20 Compound 20:(S)-3-(4-{[p-({3-[3-(p-{5-Methyl-4-[m-(tert-butylaminosulfonyl)phenylamino]-2-pyrimidinylamino}phenoxy)propyl]ureido}methyl)phenyl]methoxy}-2-isoindolinoyl)-2,6-piperidinedione

To a solution of (S)-tert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate (100 mg, 0.2 mmol) in DCM (4 mL) at RT wasadded TFA (1 mL). The mixture was stirred for 1 hour then the solventwas evaporated to give(S)-3-(4-((4-(aminomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneTFA salt which was used for the next step without further purification.MS (ESI) m/z=380.0 [M+H]⁺.

To a solution of(S)-3-(4-((4-(aminomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TFA salt (0.2 mmol) in DCM (4 mL) at RT was addedTEA (41 mg, 0.4 mmol) and 4-nitrophenyl carbonochloridate (50 mg, 0.24mmol). After stirring for 2 hrs, the mixture was concentrated to afford(S)-4-nitrophenyl4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate,which was used for the next step.

To a solution of tert-butyl(3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)carbamate (120 mg,0.2 mmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred atRT for 1 hr then the solvent was evaporated to give3-((2-((4-(3-aminopropoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)-N-(tert-butyl)benzenesulfonamide,which was used for the next step. MS (ESI) m/z=485.1 [M+H]⁺.

To a solution of phenyl (S)-4-nitrophenyl4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate(0.2 mmol) in THF (4 mL) was added TEA (0.2 mL) followed by a solutionof3-((2-((4-(3-aminopropoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)-N-(tert-butyl)benzenesulfonamide(0.2 mmol) in DCM (4 mL) and the mixture was stirred at RT overnight.The solvent was evaporated and the residue was purified by silica gelchromatography (DCM/MeOH, 10:1) and prep-HPLC as previously described toafford Compound 20 (11.5 mg, 6.5% yield) as a white solid. MS (ESI)m/z=890.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (s, 1H), 8.76 (s,1H), 8.52 (s, 1H), 8.11-8.14 (m, 2H), 7.89 (s, 1H), 7.39-7.78 (m, 8H),7.24-7.31 (m, 4H), 6.79 (d, J=8.8 Hz, 2H), 6.35 (t, J=6.0 Hz, 1H), 6.03(t, J=5.6 Hz, 1H), 5.19 (s, 2H), 5.09 (dd, J=4.8, 13.2 Hz, 1H),4.19-4.41 (m, 4H), 3.91 (t, J=6.0 Hz, 2H), 3.16 (q, J=6.4 Hz, 2H),2.85-2.94 (m, 1H), 2.53-2.58 (m, 1H), 2.42-2.49 (m, 1H), 2.11 (s, 3H),1.95-1.99 (m, 1H), 1.77-1.84 (m, 2H), 1.12 (s, 9H).

Example 21 Compound 21:(S)-3-(6-Fluoro-4-{[p-({2-[3-(p-{5-methyl-4-[m-(tert-butylsulfonylamino)phenylamino]-2-pyrimidinylamino}phenoxy)propylamino]acetylamino}methyl)phenyl]methoxy}-2-isoindolinoyl)-2,7-azepanedione

To a solution of (S)-3-aminoazepan-2-one (2.0 g, 15.9 mmol) and TEA (2.8mL, 19.9 mmol) in DMF (30 mL) at RT was added methyl2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)-5-fluorobenzoate (5.0g, 13.3 mmol) in 10 mL DMF. The mixture was stirred for 2 hrs, heated to50° C. overnight, and cooled to RT. TBAF (2.4 g, 9.31 mmol) was addedand the mixture was heated to 70° C. for 1 hr. The solvent wasevaporated and the residue was purified by silica gel chromatography(DCM/MeOH, 100:1 to 30:1) to give(S)-6-fluoro-4-hydroxy-2-(2-oxoazepan-3-yl) isoindolin-1-one (3.1 g, 83%yield) as a yellow solid. MS (ESI) m/z 279.0 [M+H]⁺.

To a solution of (S)-6-fluoro-4-hydroxy-2-(2-oxoazepan-3-yl)isoindolin-1-one (320 mg, 1.15 mmol), tert-butyl4-(hydroxymethyl)benzylcarbamate (409 mg, 1.72 mmol) andtriphenylphosphine (602 mg, 2.30 mmol) in THF (2 mL) at RT was addedDEAD (400 mg, 2.30 mmol) and the mixture was stirred for 30 min. Thesolvent was evaporated and the residue was purified by silica gelchromatography (DCM/MeOH, 100:1 to 30:1) to give (S)-tert-butyl4-(((6-fluoro-1-oxo-2-(2-oxoazepan-3-yl)isoindolin-4-yl)oxy)methyl)benzylcarbamate (430 mg, 75% yield) as a yellow solid. MS (ESI) m/z398.1 [M+H−100]⁺.

To a solution of (S)-tert-butyl 4-(((6-fluoro-1-oxo-2-(2-oxoazepan-3-yl)isoindolin-4-yl)oxy)methyl)benzylcarbamate (200 mg, 0.40 mmol) inACN/DMSO (4 mL/1 mL) at RT was added Dess-Martin periodinane (426 mg,1.00 mmol). The mixture was stirred at 80° C. overnight. After coolingto RT, 20 mL of sat. sodium thiosulfate solution was added, and themixture was extracted with DCM. Workup provided the crude product whichwas washed with tert-butyl methyl ether to afford (S)-tert-butyl4-(((2-(2,7-dioxoazepan-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate(100 mg, 50% yield) as a white solid. MS (ESI) m/z 412.0 [M+H−100]⁺.

To a solution of (S)-tert-butyl4-(((2-(2,7-dioxoazepan-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate(61 mg, 0.117 mmol) in DCM (4 mL) at RT was added TFA (1 mL). Thereaction was stirred at RT for 1 hour. The solvent was evaporated togive the amine TFA salt as a yellow gum.

The amine TFA salt was dissolved in DMA (1 mL) and2-((3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)amino)acetic acid (76 mg, 0.141 mmol) was added, followed by HOBt (23.7mg, 0.176 mmol), EDAC.HCl (34.1 mg, 0.176 mmol) and DIEA (30.0 mg, 0.234mmol). The reaction was stirred at RT for 10 hrs. The solvent wasevaporated, and the residue was purified by prep-HPLC as previouslydescribed to afford Compound 21 (10.8 mg, 10.2% yield) as a white solid.MS (ESI) m/z 936.4[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (s, 1H),8.75 (s, 1H), 8.51 (s, 1H), 8.29 (t, J=6.0 Hz, 1H), 8.14-8.11 (m, 2H),7.88 (s, 1H), 7.54-7.23 (m, 10H), 7.09-7.07 (m, 1H), 6.77 (d, J=4.8 Hz,2H), 5.20-5.17 (m, 3H), 4.40 (s, 2H), 4.30 (d, J=6.0 Hz, 2H), 3.96 (t,J=2.4 Hz, 2H), 3.15 (s, 2H), 3.09-3.00 (m, 1H), 2.67-2.54 (m, 3H),2.32-2.25 (m, 3H), 2.11 (s, 3H), 2.05-1.96 (m, 2H), 1.84-1.71 (m, 3H),1.12 (s, 9H).

Example 23 Compound 22:(S)-3-[5-(Aminomethyl)-4-{[p-(morpholinomethyl)phenyl]methoxy}-2-isoindolinoyl]-2,7-azepanedioneDitrifluoroacetic Acid

To a solution of (S)-2-(2,7-dioxoazepan-3-yl)-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindoline-5-carbonitrile (700 mg, 1.43 mmol) anddi-tert-butyl dicarbonate (625 mg, 2.87 mmol) in DMF (10 mL)/THF (15 mL)at RT was added Raney-Ni (500 mg). The mixture was stirred at RT for 48hrs under H₂. The suspension was filtered through a Celite pad andconcentrated to give the crude product which was purified by silica gelchromatography (DCM/CAN, 3:1 to 1:1) to afford(S)-tert-butyl((2-(2,7-dioxoazepan-3-yl)-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-5-yl)methyl)carbamate (800 mg, 85% yield) as a white solid. MS (ESI) m/z593.1 [M+H]⁺.

To a solution of (S)-tert-butyl((2-(2,7-dioxoazepan-3-yl)-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-5-yl)methyl)carbamate (70 mg, 0.118 mmol) inDCM (3 mL) at RT was added TFA (1.0 mL). The mixture was stirred for 1hour. The solvent was evaporated to afford Compound 22 (70 mg, 83%yield) as a white solid. MS (ESI) m/z 493.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 10.75 (s, 1H), 10.56 (s, 1H), 8.29 (s, 3H), 7.64-7.52 (m,6H), 5.36 (s, 2H), 5.28-5.24 (m, 1H), 4.85-4.73 (m, 2H), 4.39 (s, 2H),4.14 (s, 2H), 3.97 (s, 2H), 3.65 (s, 2H), 3.24-3.01 (m, 4H), 2.61-2.57(m, 2H), 2.37-2.32 (m, 1H), 2.15-2.03 (m, 2H), 1.87-1.78 (m, 1H).

Example 24 Compound 23:(S)-3-[5-({3-[3-(p-{5-Methyl-4-[m-(tert-butylaminosulfonyl)phenylamino]-2-pyrimidinylamino}phenoxy)propyl]ureido}methyl)-4-{[p-(morpholinomethyl)phenyl]methoxy}-2-isoindolinoyl]-2,6-piperidinedione

To a solution of methyl2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)-4-cyanobenzoate (3.5 g,9.096 mmol) and TEA (1.84 g, 18.2 mmol) in DMF (15 mL) at RT was added(S)-tert-butyl 4,5-diamino-5-oxopentanoate (2.6 g, 10.91 mmol). Themixture was stirred for 2 hrs then heated to 50° C. overnight. Aftercooling to RT, tetrabutylammonium fluoride (4.3 g, 13.6 mmol) added. Themixture was heated to 50° C. for 1 hr. The solvent was evaporated togive the crude product which was purified by silica gel chromatography(DCM/MeOH, 50:1 to 20:1) to give (S)-tert-butyl5-amino-4-(5-cyano-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.1g, yield; 34% yield) as a yellow solid.

To a solution of (S)-tert-butyl5-amino-4-(5-cyano-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (200mg, 0.56 mmol), 4-(4-(chloromethyl)benzyl)morpholine (188 mg, 0.835mmol) in DMF (5 mL) was added K₂CO₃ (156 mg, 1.13 mmol) and the mixturewas heated to 50° C. for 2 hrs. The solvent was evaporated and theresidue was purified by silica gel chromatography (DCM/MeOH, 50:1 to20:1) to afford (S)-tert-butyl5-amino-4-(5-cyano-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(240 mg, 80% yield) as a yellow solid.

To a solution of (S)-tert-butyl5-amino-4-(5-cyano-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (240 mg, 0.44 mmol) in DCM (5mL) at RT was added TFA (2 mL). The mixture was stirred overnight andconcentrated to afford(5)-5-amino-4-(5-cyano-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoicacid (200 mg, crude) as a yellow oil, which was used for the next stepwithout further purification.

To a solution of (S)-5-amino-4-(5-cyano-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid (200 mg, 0.41 mmol) inACN (10 mL) at RT was added CDI (200 mg, 1.22 mmol). The mixture washeated to 50° C. for 2 hrs. The solvent was evaporated, and the residuewas purified by silica gel chromatography (DCM/MeOH, 50:1 to 10:1) togive(S)-2-(2,6-dioxopiperidin-3-yl)-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindoline-5-carbonitrile(100 mg, 52% yield) as a white solid. MS (ESI) m/z 475.2 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.54 (d, J=8Hz, 1H), 7.47 (d, J=8 Hz, 2H), 7.36 (d, J=8 Hz, 2H), 5.45 (s, 2H),5.18-5.14 (m, 1H), 4.85-4.66 (m, 2H), 3.58-3.56 (m, 4H), 3.47 (s, 2H),2.96-2.89 (m, 1H), 2.65-2.60 (m, 1H), 2.47-2.44 (m, 1H), 2.36-2.33 (m,4H), 2.05-1.99 (m, 1H).

To a solution of(S)-2-(2,6-dioxopiperidin-3-yl)-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindoline-5-carbonitrile (600 mg, 1.265 mmol) anddi-tert-butyl dicarbonate (550 mg, 2.53 mmol) in DMF (5 mL) and MeOH (10mL) at RT was added Raney-Ni (300 mg). The mixture was stirred at RT for16 hrs under Hz. The suspension was filtered through a Celite pad andconcentrated to give the crude product which was purified by silica gelchromatography (DCM/MeOH, 50:1 to 20:1) to afford (S)-tert-butyl((2-(2,6-dioxopiperidin-3-yl)-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-5-yl)methyl)carbamate (400 mg, 55% yield) as a white solid. MS (ESI) m/z 579.1[M+H]⁺.

To a solution of (S)-tert-butyl((2-(2,6-dioxopiperidin-3-yl)-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-5-yl)methyl)carbamate (250 mg, 0.435 mmol)in DCM (4 mL) at RT was added TFA (1.0 mL). The mixture was stirred atRT for 1 hour. The solvent was evaporated to give(S)-3-(5-(aminomethyl)-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (250 mg, 81%yield) as a white solid. MS (ESI) m/z 479.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 11.02 (s, 1H), 10.37 (s, 1H), 8.25 (s, 3H), 7.61-7.59 (m,3H), 7.55-7.53 (m, 3H), 5.32 (s, 2H), 5.17-5.12 (m, 1H), 4.78-4.55 (m,2H), 4.36 (s, 2H), 4.14 (d, J=4.4 Hz, 2H), 3.91 (s, 2H), 3.71-3.60 (m,2H), 3.26-3.09 (m, 4H), 2.96-2.91 (m, 1H), 2.66-2.61 (m, 1H), 2.46-2.42(m, 1H), 2.04-1.99 (m, 1H).

To a solution of (S)-3-(5-(aminomethyl)-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (150 mg, 0.21 mmol) informic acid (5 mL) at RT was added formaldehyde (1 mL, 40%). The mixturewas heated to 100° C. for 1 hour. The solvent was evaporated, and theresidue was purified by prep-HPLC as previously described to give(S)-3-(5-((dimethylamino)methyl)-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(80 mg, 79% yield) as a white solid. MS (ESI) m/z 507.2 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 10.91 (s, 1H), 10.01 (s, 1H),7.68-7.54 (m, 6H), 5.37 (s, 2H), 5.17-5.06 (m, 2H), 4.85-4.78 (m, 1H),4.65-4.61 (m, 1H), 4.38 (s, 4H), 3.96 (s, 2H), 3.67 (s, 2H), 3.24-2.92(m, 4H), 2.83-2.61 (m, 7H), 2.50-2.42 (m, 1H), 2.07-2.01 (m, 1H).

To a solution of (S)-3-(5-(aminomethyl)-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (80 mg, 0.112 mmol) inTHF (5 mL) was added TEA (113 mg, 1.12 mmol). The mixture was stirred atRT for 10 min then 4-nitrophenyl(3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)carbamate (80 mg, 0.124 mmol) was added, followedby TEA (90 mg, 0.9 mmol). After stirring at RT for 1 h, the mixture wasconcentrated and the residue was purified by prep-HPLC as previouslydescribed to afford Compound 23 (40 mg, 36% yield) as a white solid. MS(ESI) m/z 989.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 8.79(s, 1H), 8.54 (s, 1H), 8.13 (s, 2H), 7.90 (s, 1H), 7.57-7.33 (m, 11H),6.79 (d, J=8 Hz, 2H), 6.36-6.33 (m, 1H), 6.16-6.13 (m, 1H), 5.16-5.09(m, 3H), 4.65-4.54 (m, 2H), 4.33 (d, J=4 Hz, 2H), 3.93-3.90 (m, 2H),3.56 (s, 4H), 3.46 (s, 2H), 3.18-3.15 (m, 2H), 2.97-2.88 (m, 1H),2.62-2.58 (m, 1H), 2.34 (s, 4H), 2.12 (s, 3H), 2.01-1.92 (m, 1H), 1.89(s, 1H), 1.82-1.79 (m, 2H), 1.12 (s, 9H).

Example 25 Compound 24:(S)-3-(4-{[p-({2-[3-(p-{5-Methyl-4-[m-(tert-butylaminosulfonyl)phenylamino]-2-pyrimidinylamino}phenoxy)propylamino]acetylamino}methyl)phenyl]methoxy}-2-isoindolinoyl)-2,6-piperidinedione

To a solution of2-((3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)amino)aceticacid (54 mg, 0.1 mmol) and(S)-3-(4-((4-(aminomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.1 mmol) in DMF (2 mL) at RT was added DIEA (26 mg, 0.2 mmol), HOBt(20 mg, 0.15 mmol) and EDAC.HCl (29 mg, 0.15 mmol) and the mixture wasstirred overnight. The solvent was evaporated, and the residue waspurified by prep-TLC (DCM/MeOH, 10:1) to afford Compound 24 (6.0 mg,6.7% yield) as a white solid. MS (ESI) m/z=904.3 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 10.95 (s, 1H), 8.76 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H),8.11-8.14 (m, 2H), 7.89 (s, 1H), 7.40-7.54 (m, 8H), 7.27-7.31 (m, 4H),6.78 (d, J=9.2 Hz, 2H), 5.20 (s, 2H), 5.09 (dd, J=5.2, 13.2 Hz, 1H),4.21-4.41 (m, 4H), 3.96 (t, J=6.0 Hz, 2H), 2.85-2.94 (m, 1H), 2.76 (t,J=6.0 Hz, 2H), 2.53-2.58 (m, 1H), 2.40-2.45 (m, 2H), 2.11 (s, 3H),1.95-1.98 (m, 2H), 1.87-1.90 (m, 2H), 1.12 (s, 9H).

Example 26 Compound 25:(S)-3-(6-Fluoro-4-{[p-({2-[3-(p-{5-methyl-4-[m-(tert-butylaminosulfonyl)phenylamino]-2-pyrimidinylamino}phenoxy)propylamino]acetylamino}methyl)phenyl]methoxy}-2-isoindolinoyl)-2,6-piperidinedione

To a solution of methyl 5-fluoro-3-hydroxy-2-methylbenzoate (3.2 g, 17.4mmol) and imidazole (2.9 g, 43.5 mmol) in DMF (6 mL) at RT was addedtert-butyldimethylsilyl chloride (3.1 g, 20.8 mmol). The mixture wasstirred at 60° C. for 1 hour then cooled to RT and extracted withtert-butyl methyl ether. The combined organic layers were dried overanhydrous Na₂SO₄, filtered, and concentrated to give methyl3-((tert-butyldimethylsilyl)oxy)-5-fluoro-2-methylbenzoate (5.2 g crude)as a yellow oil which was used for the next step without furtherpurification.

To a solution of methyl3-((tert-butyldimethylsilyl)oxy)-5-fluoro-2-methylbenzoate (3.2 g, 10.7mmol) in carbon tetrachloride (30 mL) at RT was added NBS (2.9 g, 16.1mmol) and 2,2′-azobis(2-methylpropionitrile) (700 mg, 4.3 mmol). Themixture was stirred at 80° C. for 6 hrs. The solvent was evaporated togive the crude product which was purified by silica gel chromatography(petroleum ether/EtOAc, 10:1) to afford methyl2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)-5-fluorobenzoate (4.0g, quant. yield) as a yellow oil.

To a solution of methyl2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)-5-fluorobenzoate (1.0g, 2.66 mmol) and TEA (0.7 mL, 5.32 mmol) in DMF (6 mL) at RT was addedtert-butyl 4,5-diamino-5-oxopentanoate (696 mg, 2.92 mmol) in 4 mL DMF.The mixture was stirred for 2 hrs, then heated to 80° C. overnight. Thesolvent was evaporated to give the crude product which was purified bysilica gel chromatography (DCM/MeOH, 50:1 to 20:1) to afford tert-butyl5-amino-4-(6-fluoro-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.0g crude) as a white solid. MS (ESI) m/z 297.0 [M+H−56]⁺.

To a solution of tert-butyl5-amino-4-(6-fluoro-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (500mg, 1.42 mmol), 4-(hydroxymethyl)benzonitrile (283 mg, 2.13 mmol) andtriphenylphosphine (930 mg, 3.55 mmol) in THF (4 mL) at RT was addedDEAD (617 mg, 3.55 mmol). The mixture was stirred at RT for 2 hrs. Thesolvent was evaporated, and the residue was purified by silica gelchromatography (DCM/MeOH, 100:1 to 50:1) to give tert-butyl5-amino-4-(4-((4-cyanobenzyl)oxy)-6-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoate(350 mg, 52% yield) as a yellow solid. MS (ESI) m/z 412.0 [M+H−56]⁺.

To a solution of tert-butyl5-amino-4-(4-((4-cyanobenzyl)oxy)-6-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoate(350 mg, 0.75 mmol) in DCM (4 mL) at RT was added TFA (4 mL). Themixture was stirred at RT overnight. The solvent was evaporated to give5-amino-4-(4-((4-cyanobenzyl)oxy)-6-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoicacid (400 mg, crude) as a yellow solid which was used for the next stepwithout further purification. MS (ESI) m/z 412.0 [M+H]⁺.

To a solution of5-amino-4-(4-((4-cyanobenzyl)oxy)-6-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoicacid (400 mg, 0.75 mmol) in ACN (10 mL) at RT was added CDI (485 mg,2.99 mmol). The mixture was stirred at 95° C. for 3.5 hrs. The solventwas evaporated to give the crude product which was purified by silicagel chromatography (DCM/MeOH, 100:1 to 50:1) to afford4-(((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)benzonitrile(200 mg, 68%) as a white solid. MS (ESI) m/z 394.0 [M+H]⁺.

To a solution of4-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)benzonitrile (200 mg, 0.51 mmol) and di-tert-butyldicarbonate (166 mg, 0.76 mmol) in THF (6 mL) at RT was added Raney-Ni(80 mg). The mixture was stirred at RT under H₂ overnight. Thesuspension was filtered through a Celite pad and the filtrate wasconcentrated to give the crude product which was purified by silica gelchromatography (DCM/MeOH, 100:1 to 20:1) to afford tert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate(90 mg, 35% yield) as a white solid. MS (ESI) m/z 398.0 [M+H−100]⁺.

To a solution of tert-butyl4-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate (80 mg, 0.161 mmol) in DCM (4 mL) at RT was addedTFA (1 mL). The reaction was stirred for 1 hour. The solvent wasevaporated, and the residue was dried to give the amine TFA salt as ayellow gum.

The amine TFA salt was dissolved in DMA (1 mL) and2-((3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)amino)acetic acid (109 mg, 0.161 mmol) was added, followed by HOBt (32.6mg, 0.242 mmol), EDAC.HCl (46.5 mg, 0.242 mmol) and DIEA (41.5 mg, 0.322mmol) and the mixture was stirred at RT for 10 hrs. The solvent wasevaporated, and the residue was purified by prep-HPLC as previouslydescribed to afford Compound 25 (23.9 mg, 16% yield) as a white solid.MS (ESI) m/z 922.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H),8.75 (s, 1H), 8.52 (s, 1H), 8.29 (t, J=6.4 Hz, 1H), 8.14-8.11 (m, 2H),7.88 (s, 1H), 7.55-7.23 (m, 10H), 7.10-7.08 (m, 1H), 6.77 (d, J=5.2 Hz,2H), 5.19 (s, 2H), 5.08 (dd, J=8.4, 13.6 Hz, 1H), 4.37-4.18 (m, 4H),3.95 (t, J=6.4 Hz, 1H), 3.16 (s, 2H), 2.93-2.83 (m, 1H), 2.66-2.57 (m,3H), 2.11 (s, 3H), 2.02-1.93 (m, 1H), 1.86-1.79 (m, 3H), 1.12 (s, 9H).

Example 27 Compound 26:(S)-3-(4-{2-[p-(Morpholinomethyl)phenyl]ethoxy}-2-isoindolinoyl)-2,7-azepanedione

To a solution of methyl 4-(2-methoxy-2-oxoethyl)benzoate (5 g, 0.24 mol)in THF (25 mL) at 0° C. was added lithium aluminium hydride (1M solutionin THF, 36 mL) dropwise. The mixture was stirred at 0° C. for 2 hrs thenthe reaction was quenched by Na₂SO₄ decahydrate, diluted with EtOAc andfiltered. The filtrate was washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated to give2-(4-(hydroxymethyl)phenyl)ethanol (3 g, crude) as a yellow oil. ¹H NMR(400 MHz, DMSO-d₆) δ 7.13-7.23 (m, 4H), 5.08 (t, J=5.6 Hz, 1H), 4.61 (t,J=5.2, 8.4 Hz, 1H), 4.44 (d, J=7.0 Hz, 2H), 3.54-3.59 (m, 2H), 2.69 (t,J=7.2 Hz, 2H).

To a stirred solution of 2-(4-(hydroxymethyl)phenyl)ethanol (3 g, crude,19.7 mmol) in chloroform (30 mL) was added manganese dioxide (6.9 g, 79mmol). The mixture was stirred at 70° C. overnight then filtered andconcentrated. The residue was purified by silica gel chromatography(petroleum/EtOAc, 5:1) to give 4-(2-hydroxyethyl)benzaldehyde (1.3 g,38% over 2 steps) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 9.90 (s,1H), 7.76 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 3.84 (t, J=6.4 Hz,2H), 2.88 (t, J=6.4 Hz, 2H).

To a stirred solution of 4-(2-hydroxyethyl)benzaldehyde (1.3 g, 8.67mmol) in DCM (20 mL) was added tosyl chloride (2.5 g, 13 mmol) and TEA(4.8 mL). The mixture was stirred at RT overnight then evaporated andpurified by silica gel chromatography (petroleum/EtOAc, 5:1) to give4-formylphenethyl 4-methylbenzenesulfonate (2 g, 77% yield) as a whitesolid.

To a stirred solution of(S)-4-hydroxy-2-(2-oxoazepan-3-yl)isoindolin-1-one (250 mg, 0.96 mmol)and 4-formylphenethyl 4-methylbenzenesulfonate (392 mg, 1.15 mmol) inACN (5 mL) at RT was added K₂CO₃ (400 mg, 2.88 mmol). After stirring at80° C. overnight, the mixture was concentrated, and the residue waspurified by silica gel chromatography (DCM/MeOH, 50:1) to give(S)-4-(2-((1-oxo-2-(2-oxoazepan-3-yl)isoindolin-4-yl)oxy)ethyl)benzaldehyde(100 mg, 27% yield) as a colorless oil. MS (ESI) m/z=393.1 [M+H]⁺.

To a solution of (S)-4-(2-((1-oxo-2-(2-oxoazepan-3-yl)isoindolin-4-yl)oxy)ethyl)benzaldehyde (100 mg, 0.25 mmol) in 1,2-dichloroethane (6 mL)and DMSO (1 mL) at RT was added Dess-Martin reagent (530 mg, 1.25 mol).The mixture was stirred at 80° C. overnight then cooled to RT andfiltered. The filtrate was quenched with sat. sodium thiosulfatesolution and extracted with DCM. Workup and purification by prep-TLC(EtOAc) to give(S)-4-(2-((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl) oxy)ethyl)benzaldehyde (40 mg, 38% yield) as a white solid. MS (ESI) m/z=407.0[M+H]⁺.

To a solution of(S)-4-(2-((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)oxy)ethyl)benzaldehyde (40 mg, 0.1 mmol) and morpholine (26 mg, 0.3mmol) in DCM (5 mL) at RT was added sodium triacetoxyborohydride (106mg, 0.5 mmol). The mixture was stirred overnight then concentrated. Theresidue was purified by prep-HPLC as previously described to affordCompound 26 (18 mg, 38% yield) as a white solid. MS (ESI) m/z=478.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H), 7.45 (t, J=8.0 Hz,1H), 7.23-7.30 (m, 6H), 5.22 (dd, J=4.8, 12.4 Hz, 1H), 4.36 (s, 2H),4.32 (t, J=6.8 Hz, 2H), 3.55 (t, J=4.4 Hz, 4H), 3.41 (s, 2H), 3.03-3.08(m, 3H), 2.59-2.60 (m, 1H), 2.29-2.32 (m, 5H), 1.99-2.10 (m, 2H),1.74-1.84 (m, 1H).

Example 28 Compound 27:(S)-3-[5-({3-[3-(p-{5-Methyl-4-[m-(tert-butylaminosulfonyl)phenylamino]-2-pyrimidinylamino}phenoxy)propyl]ureido}methyl)-4-{[p-(morpholinomethyl)phenyl]methoxy}-2-isoindolinoyl]-2,7-azepanedione

To a solution of (S)-3-(5-(aminomethyl)-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)azepane-2,7-dione (50 mg, 0.084 mmol) in THF(5 mL) at RT was added TEA (68 mg, 0.672 mmol) followed by a suspensionof 4-nitrophenyl(3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)carbamate (54 mg, 0.084 mmol) in THF (1 mL). The mixture was stirred for3 hrs. The solvent was evaporated, and the residue was purified bysilica gel chromatography eluting with DCM/MeOH from 0% to 10% to givethe crude product (70 mg) as a white gum, which was further purified byprep-HPLC as previously described to afford Compound 27 (27.7 mg, 33%yield) as a white solid. MS (ESI) m/z 1003.4[M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 10.70 (s, 1H), 8.76 (s, 1H), 8.53 (s, 1H), 8.13 (s, 1H), 7.90(s, 1H), 7.59-7.38 (m, 9H), 7.34 (d, J=8.0 Hz, 2H), 6.79 (d, J=8.8 Hz,2H), 6.34 (t, J=6.0 Hz, 1H), 6.13 (t, J=5.6 Hz, 1H), 5.23 (dd, J=4.8,12.0 Hz, 1H), 5.18 (s, 2H), 4.65 (s, 2H), 4.33 (d, J=5.2 Hz, 2H), 3.92(t, J=6.0 Hz, 2H), 3.58-3.55 (m, 4H), 3.47 (s, 2H), 3.20-3.15 (m, 2H),3.12-3.04 (m, 1H), 2.60-2.56 (m, 1H), 2.35-2.31 (m, 5H), 2.12 (s, 3H),2.08-1.99 (m, 1H), 1.86-1.78 (m, 4H), 1.12 (s, 9H).

PBMC Assays

Frozen primary blood mononuclear cells (PBMCs) were purchased fromAllCells. Cells were quick thawed, washed once with RPMI-1640/10% FBS.

1% Penicillin/1% Streptomycin and plated in 96 well plates at 200,000cells per well. Cells were pretreated with DMSO only, or Compound 1 for1 hour and then induced with 100 ng/mL lipopolysaccharide (LPS) for18-24 hrs. The supernatant was analyzed for IL-1 beta, IL-6, and TNFα,using Meso Scale assay according to manufacturer's protocol. Thenegative control wells were treated with DMSO.

For the IL-2 analysis, 96 well plates were precoated with 1 μg/mLanti-human CD3 antibody (OKT3, eBioscience Inc.). After washing withPBS, Compound 1 was added (50 μL/well) followed by PBMCs diluted at 3-4million cells/mL (150 μL/well). Plates were incubated for 24 hr and thesupernatants collected for Mesoscale IL-2 analysis.

Compound activity was measured as fold difference from the DMSO control.IL-1β activity is shown in FIG. 1; IL-6 activity is shown in FIG. 2;TNFα activity is shown in FIG. 3; and IL-2 activity is shown in FIG. 4.Additional data for compounds (shown as percent inhibition) at 10 μM isshown in Table 1; at 1 μM in Table 2; and at 0.1 μM in Table 3.Additional data for IL-activity (measured as fold-change in activity) isshown in Tables 4-6.

TABLE 1 Compound IL-1β IL-6 TNFα No. % Inhibition % Inhibition %Inhibition 3 93 77 94 12 99.6 100 99 14 65 42 83 15 81 50 87 16 52 78 7517 100 100 100 18 83 45 89 21 11 7 30 24 23 1 23 28 5 2 5

TABLE 2 Compound IL-1β IL-6 TNFα No. % Inhibition % Inhibition %Inhibition 1 88 71 93 2 86 67 90 3 93 79 93 4 86 67 90 6 92 76 83 12 230 32 13 51 59 84 14 76 37 82 15 59 10 65 16 24 5 27 17 75 35 75 18 80 4983 19 65 43 73 20 43 5 57 21 6 8 20 22 74 27 80 23 79 32 88 24 7 9 10 258 32 25 26 81 8 87 27 62 4 72 28 6 5 9 29 2 11 11

TABLE 3 Compound IL-1β IL-6 TNFα No. % Inhibition % Inhibition %Inhibition 1 83 63 89 2 72 43 81 3 91 72 91 4 72 43 81 5 64 37 55 6 6842 62 7 71 55 62 8 73 56 63 9 74 51 62 10 52 27 48 11 21 12 21 19 22 1241 20 30 1 43 22 69 23 78 23 35 23 48 25 0 3 13 26 78 5 82 27 50 5 60 290 11 12

TABLE 4 IL-2 Compound 10 μM Compound No. Fold Change 12 0.7 13 0.1 142.3 15 2.1 16 0.2 17 0.1 18 3.3 21 1 24 1 28 1.9

TABLE 5 IL-2 Compound at 1 μM Compound No. Fold Change 1 0.8 2 2.3 3 0.74 2.3 5 2.1 6 2.5 7 1.1 8 2.3 9 1.6 10 2.1 11 1.9 12 1 13 0.3 14 2.2 151.9 16 0.7 17 1.5 18 3.2 19 2.4 20 1.4 21 0.9 22 2.4 23 1.3 24 1 25 1 262.7 27 1.5 28 1.5 29 0.9

TABLE 6 IL-2 Compound at 0.1 μM Compound No. Fold Change 1 2.1 2 1.3 3 24 1.3 5 1.2 6 1 7 1 8 1.8 9 1.6 10 1.9 11 1.2 19 1.5 20 0.9 22 2 23 0.925 0.9 26 2.6 27 1.3 29 0.9

Western Blot Analysis

Western Blot Protocol: Jurkat cells were grown in RPMI 1640 supplementedwith streptomycin, penicillin and 10% fetal bovine serum.

Jurkat cells were cultured at approximately 10⁶ cells per mL, DMSO orthe indicated compound at the indicated concentration was added to thecells and allowed to incubate for the indicated period. Whole cellextracts were prepared with RIPA Reagent according to manufacturer'sprotocol (Pierce). Briefly, ˜5×10⁶ cells were washed once in PBS, thecell pellet was resuspended in RIPA solution and allowed to incubate for10 min at room temperature. Cell debris was removed by centrifugationand the cleared whole cell lysate was transferred to a new tube forfurther analysis.

For Western blot analysis, whole cell extracts were separated on 4-12%SDS-polyacrylamide gels, transferred to nitrocellulose and probed withthe indicated primary antibodies. Membranes were subsequently washed andprobed with the appropriate horseradish peroxidase (HRP)-conjugatedsecondary antibody. The signal was detected using the WesternBrightSirius Reagent (Advansta). Results are shown in FIG. 5A and FIG. 5B.

The following antibodies were used in these studies:

Beta-actin: Mouse anti-b-Actin was obtained from Cell Signaling(8H10D10).CK1α goat polyclonal antibody: Santa Cruz Biotechnology, sc-6477 (SantaCruz, Calif.)Ikaros rabbit monoclonal antibody: Cell Signaling, #9034, D10E5 (Danver,Mass.)Donkey anti-goat IgG-HRP: Santa Cruz Biotechnology, sc-2056 (Santa Cruz,Calif.)Goat anti-rabbit IgG-HRP: Cell Signaling, #7074 (Danver, Mass.)Goat anti-mouse IgG-HRP: Sigma, A4416 (St. Louis, Mo.)

Cell Viability Assay

Molm-13 and MV-4-11 cells were cultivated in RPMI-1640 (10% FBS/1%pen-strep) and were plated in white walled 96-well plates at 20,000cells/well.

Cells were treated with compound at the indicated concentration or DMSO(control) and the cultures were incubated for 3 days at 37° C. and 5%CO₂. Following the incubation period, 100 μL of CellTiterGlow (CTG)reagent (CellTiter-Glo® Luminescent Cell Viability Assay, Promega(Madison, Wis.)) was added to each well. Following a 10 min incubationwith shaking, luminescence was measured using a Victor WallacLuminometer.

Molm-13 cellular proliferation activity is shown in Tables 7-9. MV-4-11cellular proliferation activity in shown in Tables 10 and 11.

TABLE 7 Molm-13 Proliferation Compound at 10 μM Compound No. %Inhibition 1 37 2 30 3 29 5 40 6 91 8 16 9 34 10 38 18 99

TABLE 8 Molm-13 Proliferation Compound at 1 μM Compound No. % Inhibition1 15 2 5 3 1 13 29 14 35 20 99 22 56 23 30 26 66 27 37

TABLE 9 Molm-13 Proliferation Compound at 0.1 μM Compound No. %Inhibition 1 30 20 93 22 31 26 21

TABLE 10 MV-4-11 Proliferation Compound at 10 μM Compound No. %Inhibition 1 5 2 16 3 20 4 0 5 3 6 76 7 0 8 0 9 10 10 35 11 0 12 35 1350 14 0 15 99 16 99 17 98 18 99 19 0 20 88 21 97 22 4 23 79 24 80 25 9026 23 27 36

TABLE 11 MV-4-11 Proliferation Compound at 1 μM Compound No. %Inhibition 1 2 2 6 3 0 4 0 5 1 6 0 7 0 8 0 9 2 10 1 11 0 12 0 13 0 14 015 38 16 0 17 31 18 99 19 0 20 77 21 0 22 2 23 8 24 44 25 54 26 2 27 10

While the disclosure has been illustrated and described in detail in thedrawings and foregoing description, such illustration and descriptionare to be considered illustrative or exemplary and not restrictive. Thedisclosure is not limited to the disclosed embodiments. Variations tothe disclosed embodiments can be understood and effected by thoseskilled in the art in practicing the claimed disclosure, from a study ofthe drawings, the disclosure and the appended claims.

All references cited herein are incorporated herein by reference intheir entirety. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

Unless otherwise defined, all terms (including technical and scientificterms) are to be given their ordinary and customary meaning to a personof ordinary skill in the art, and are not to be limited to a special orcustomized meaning unless expressly so defined herein. It should benoted that the use of particular terminology when describing certainfeatures or aspects of the disclosure should not be taken to imply thatthe terminology is being re-defined herein to be restricted to includeany specific characteristics of the features or aspects of thedisclosure with which that terminology is associated.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ ‘including but not limited to,’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; adjectives suchas ‘known’, ‘normal’, ‘standard’, and terms of similar meaning shouldnot be construed as limiting the item described to a given time periodor to an item available as of a given time, but instead should be readto encompass known, normal, or standard technologies that may beavailable or known now or at any time in the future; and use of termslike ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction of the invention, but instead as merely intended to highlightalternative or additional features that may or may not be utilized in aparticular embodiment of the invention. Likewise, a group of itemslinked with the conjunction ‘and’ should not be read as requiring thateach and every one of those items be present in the grouping, but rathershould be read as ‘and/or’ unless expressly stated otherwise. Similarly,a group of items linked with the conjunction ‘or’ should not be read asrequiring mutual exclusivity among that group, but rather should be readas ‘and/or’ unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article “a” or “an” does not exclude aplurality. A single processor or other unit may fulfill the functions ofseveral items recited in the claims. The mere fact that certain measuresare recited in mutually different dependent claims does not indicatethat a combination of these measures cannot be used to advantage. Anyreference signs in the claims should not be construed as limiting thescope.

It will be further understood by those within the art that if a specificnumber of an introduced claim recitation is intended, such an intentwill be explicitly recited in the claim, and in the absence of suchrecitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould typically be interpreted to mean at least the recited number(e.g., the bare recitation of “two recitations,” without othermodifiers, typically means at least two recitations, or two or morerecitations). Furthermore, in those instances where a conventionanalogous to “at least one of A, B, and C, etc.” is used, in generalsuch a construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, and C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). In those instances where aconvention analogous to “at least one of A, B, or C, etc.” is used, ingeneral such a construction is intended in the sense one having skill inthe art would understand the convention (e.g., “a system having at leastone of A, B, or C” would include but not be limited to systems that haveA alone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term ‘about.’ Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Q₁ is CH₂, O,NR₂, S, or a bond; Q₂ is CH₂ or a bond; X is CH₂ or C═O; X₁ is hydrogen,deuterium, methyl, or fluoro; Ring B is

wherein Y₁ is N or CR_(3A); Y₂ is N or CR_(3B); Y₃ is N or CR_(3C); Y₄is N or CR_(3D); Y₅ is N or CR_(3E); each R₁ is independently deuterium,hydroxyl, halogen, nitro, a substituted or unsubstituted amino, asubstituted or unsubstituted C₁-C₆ alkoxy, a substituted orunsubstituted C₁-C₆ alkyl, a substituted or unsubstituted C₂-C₆ alkenyl,a substituted or unsubstituted C₃-C₈ cycloalkyl, a substituted orunsubstituted 3 to 10 membered heterocyclyl, a substituted orunsubstituted C₆-C₁₀ aryl, a substituted or unsubstituted 5 to 10membered heteroaryl, or L-Y; R₂ is Hydrogen, deuterium, a substituted orunsubstituted C₁-C₆ alkyl, a substituted or unsubstituted C₂-C₆ alkenyl,acyl, or —(SO₂)—C₁-C₆ alkyl; each R_(3A), R_(3B), R_(3C), R_(3D), andR_(3E) is independently hydrogen, deuterium, hydroxyl, halogen, nitro, asubstituted or unsubstituted amino, a substituted or unsubstituted C₁-C₆alkoxy, a substituted or unsubstituted C₁-C₆ alkyl, a substituted orunsubstituted C₂-C₆ alkenyl, a substituted or unsubstituted C₃-C₈cycloalkyl, a substituted or unsubstituted 3 to 10 memberedheterocyclyl, a substituted or unsubstituted alkoxyalkyl, a substitutedor unsubstituted cycloalkylalkyl, a substituted or unsubstitutedheterocyclylalkyl, a substituted or unsubstituted aralkyl, a substitutedor unsubstituted heteroaralkyl, or L-Y; m is 0, 1, 2, or 3; n is 1, 2,or 3; L is —Z₁—(R₄)_(t)—Z₂—; —Z₁—(R₄—O—R₄)_(t)—Z₂—;—Z₁(R₄—NH—R₄)_(t)—Z₂—; —Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂—;—Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂—; or —Z₁—(R₄—(CONH)—R₄)_(t)—Z₂—; Z₁ and Z₂are independently selected from —NH—; —O—; —CH₂—; —NH(CO)—; —(CO)NH—;—CH₂NH—; —NHCH₂—; —(CO)NHCH₂—; —CH₂CH₂NH—; —CH₂NH(CO)—; or —NHCH₂CH₂—;each R₄ is independently an unsubstituted C₁-C₆ alkylene; t is 1, 2, 3,4, 5, or 6; and Y is

wherein Y is derivatized to attach to L; and wherein at least one of Y₁,Y₂, Y₃, Y₄, and Y₅ is Y₅ is respectively R_(3A), R_(3B), R_(3C), R_(3D),or R_(3E); when Q₁ is CH₂ or a bond, then one or more of R_(3A), R_(3B),R_(3C), R_(3D), or R_(3E) is not hydrogen; when R₁ is L-Y, none ofR_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) is L-Y; and when Q₂ is abond, Q₁ is a bond or CH₂; and when Q₁ is a bond, X₁ is hydrogen ormethyl, and Q₂ is CH₂; then m is not 0; or when Q₁ is a bond, X₁ ishydrogen or methyl, and Q₂ is CH₂; then one of R₁, R_(3A), R_(3B),R_(3C), R_(3D), and R_(3E) is L-Y.
 2. (canceled)
 3. The compound ofclaim 1, wherein X is CH₂.
 4. The compound of claim 1, wherein X is C═O.5. The compound of claim 1, wherein X₁ is hydrogen. 6-13. (canceled) 14.The compound of claim 1, wherein Q₁ is CH₂.
 15. (canceled) 16.(canceled)
 17. The compound of claim 1, wherein Q₁ is a bond.
 18. Thecompound of claim 1, wherein Q₂ is CH₂.
 19. The compound of claim 1,wherein Q₂ is a bond.
 20. The compound of claim 1, wherein n is
 1. 21.The compound of claim 1, wherein n is
 2. 22. The compound of claim 1,wherein m is
 1. 23. (canceled)
 24. (canceled)
 25. The compound of claim1, wherein m is
 0. 26. The compound of claim 1, wherein each R₁ isindependently halogen, a substituted or unsubstituted amino, asubstituted or unsubstituted C₁-C₆ alkoxy, a substituted orunsubstituted C₃-C₈ cycloalkyl, or a substituted or unsubstituted C₁-C₆alkyl.
 27. (canceled)
 28. The compound of claim 26, wherein each R₁ isindependently fluoro, chloro, —NH₂, —NH(CH₃), —N(CH₃)₂, —CF₃, —OCH₃,—OCH₂CH₃, —OCH(CH₃)₂, —CH₃, —CH₂CH₃, —CH(CH₃)₂, an unsubstitutedcyclopropyl, an unsubstituted cyclobutyl, or an unsubstitutedcyclopentyl.
 29. The compound of claim 1, wherein Ring B is selectedfrom:


30. (canceled)
 31. The compound of claim 1, wherein each of R_(3A),R_(3B), R_(3C), R_(3D), and R_(3E) is independently hydrogen, hydroxyl,halogen, nitro, an unsubstituted amino, an unsubstituted C₁-C₆haloalkyl, an unsubstituted C₁-C₆ alkoxy, an unsubstituted C₁-C₆ alkyl,a substituted or unsubstituted C₃-C₈ cycloalkyl, a substituted orunsubstituted 3 to 10 membered heterocyclyl, a substituted orunsubstituted alkoxyalkyl, a substituted or unsubstitutedcycloalkylalkyl, a substituted or unsubstituted heterocyclylalkyl, asubstituted or unsubstituted aralkyl or a substituted or unsubstitutedheteroaralkyl.
 32. (canceled)
 33. (canceled)
 34. The compound of claim1, wherein one of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) is halogen,an unsubstituted C₁-C₆ haloalkyl, an unsubstituted C₁-C₆ alkoxy, anunsubstituted C₁-C₆ alkyl, an unsubstituted 3 to 10 memberedheterocyclyl, or an unsubstituted 3 to 10 membered heterocyclylalkyl andthe other of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) are hydrogen.35. The compound of claim 1, wherein one of R_(3A), R_(3B), R_(3C),R_(3D), and R_(3E) is fluoro, chloro, —CF₃, —OCH₃, an unsubstitutedC₁-C₆ alkyl, an unsubstituted 3 to 10 membered heterocyclyl, or anunsubstituted 3 to 10 membered heterocyclylalkyl and the other ofR_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) groups are hydrogen.
 36. Thecompound of claim 1, wherein one of R_(3A), R_(3B), R_(3C), R_(3D), andR_(3E) is

and the other of R_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) groups arehydrogen.
 37. (canceled)
 38. The compound of claim 1, wherein one ofR_(3A), R_(3B), R_(3C), R_(3D), and R_(3E) is L-Y.
 39. The compound ofclaim 1, wherein Y₃ is C-L-Y.
 40. The compound of claim 1, wherein L is—Z₁—(R₄—O—R₄)_(t)—Z₂— or —Z₁(R₄—NH—R₄)_(t)—Z₂—.
 41. (canceled)
 42. Thecompound of claim 1, wherein L is Z₁—(R₄—(NHCO)—R₄)_(t)—Z₂—;—Z₁—(R₄—(CONH)—R₄)_(t)—Z₂—; or —Z₁—(R₄—(NHC(O)NH)—R₄)_(t)—Z₂—. 43.(canceled)
 44. The compound of claim 1, wherein Z₁ and Z₂ areindependently selected from —NH—; —O—; —CH₂—; —NH(CO)—; —(CO)NH—;—CH₂NH(CO)—; —CH₂NH—; —NHCH₂— and NHCH₂CH₂—. 45-56. (canceled)
 57. Thecompound of claim 1, wherein each R₄ is independently an unsubstitutedC₁-C₄ alkylene.
 58. (canceled)
 59. The compound of claim 1, wherein t is1 or
 2. 60. (canceled)
 61. (canceled)
 62. (canceled)
 63. (canceled) 64.(canceled)
 65. The compound of claim 1, having a structural formulaselected from:

or a pharmaceutically acceptable salt of any of the foregoing.
 66. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable excipient.
 67. A method of inhibiting the activity of acytokine, comprising contacting a cell with an effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof;wherein the cytokine is selected from IL-1β, IL-2, IL-6, and TNFα.68-94. (canceled)